Tetracyclic heteroatom containing derivatives useful as sex steroid hormone receptor modulators

ABSTRACT

The present invention is directed to novel tetracyclic heteroatom containing derivatives, pharmaceutical compositions containing them, their use in the treatment of disorders mediated by one or more sex steroid hormone receptors and processes for their preparation.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.12/707,388, filed on Feb. 17, 2010, issued as U.S. Pat. No. 8,580,840,which is a divisional of U.S. application Ser. No. 11/968,963, filed onJan. 3, 2008, issued as U.S. Pat. No. 7,696,239 which is a divisional ofU.S. application Ser. No. 11/228,562, filed on Sep. 16, 2005, issued asU.S. Pat. No. 7,338,973 and claims the benefit of U.S. ProvisionalApplication 60/611,376, filed on Sep. 20, 2004.

The complete disclosures of the aforementioned related U.S. patentapplications are hereby incorporated herein by reference for allpurposes.

FIELD OF THE INVENTION

The present invention is directed to novel tetracyclic heteroatomcontaining derivatives, pharmaceutical compositions containing them andtheir use in the treatment of disorders mediated by one or more sexsteroid hormone receptors. The compounds of the present invention areselective estrogen, selective androgen and/or progestin receptormodulators.

BACKGROUND OF THE INVENTION

Estrogens are a group of female hormones essential for the reproductiveprocess and for the development of the uterus, breasts, and otherphysical changes associated with puberty. Estrogens have an effect onvarious tissues throughout a woman's body, not only those involved inthe reproductive process, such as the uterus, breasts, and externalgenitalia, but also tissues in the central nervous system, bones, theliver, skin, and the urinary tract. The ovaries produce most of theestrogens in a woman's body.

Menopause is defined as the permanent cessation of menses due to loss ofovarian follicular function and the near complete termination ofestrogen production. The midlife transition of menopause ischaracterized by a decrease in estrogen that provokes both short-termand long-term symptoms with the vasomotor, urogenital, cardiovascular,skeletal and central nervous systems, such as hot flushes, urogenitalatrophy, increased risk of cardiovascular disease, osteoporosis,cognitive and psychological impairment, including an increased risk ofcognitive disorders and Alzheimer's disease (AD).

Seventy-five percent of all women experience some occurrence ofvasomotor symptoms associated with the onset of menopause such as bodysweating and hot flushes. These complaints may begin several yearsbefore menopause and in some women may continue for more than 10 years,either relatively constant, or as instant attacks without a definable,provoking cause.

Urogenital symptoms associated with the onset of menopause involving thevagina include a sensation of dryness, burning, itching, pain duringintercourse, superficial bleeding and discharge, along with atrophy andstenosis. Symptoms involving the urinary tract include a burningsensation during urination, frequent urgency, recurrent urinary tractinfections, and urinary incontinence. These symptoms have been reportedto occur in up to 50% of all women near the time of menopause and aremore frequent a few years after menopause. If left untreated, theproblems can become permanent.

Heart attack and stroke are major causes of morbility and mortalityamong senior women. Female morbility from these diseases increasesrapidly after menopause. Women who undergo premature menopause are atgreater coronary risk than menstruating women of similar age. Thepresence of serum estrogen has a positive effect on serum lipids. Thehormone promotes vasodilation of blood vessels, and enhances theformation of new blood vessels. Thus the decrease in serum estrogenlevels in postmenopausal women results in an adverse cardiovasculareffect. Additionally, it is theorized that differences in the ability ofblood to coagulate may account for the observed difference in theoccurrence of heart disease before and after menopause.

The skeleton is under a continuous process of bone degeneration andregeneration in a carefully regulated interaction among the bone cells.These cells are directly affected by estrogen. Estrogen deficiencyresults in a loss of bone structure, and decrease in bone strength.Rapid loss of bone mass during the year immediately following menopauseleads to postmenopausal osteoporosis and increased risk of fracture.

Estrogen deficiency is also one of the causes for the degenerativechanges in the central nervous system and may lead to Alzheimer'sdisease (AD) and a decline of cognition. Recent evidence suggests anassociation between estrogen, menopause and cognition. Moreparticularly, it has been reported that estrogen replacement therapy andthe use of estrogen in women may prevent the development of AD andimprove cognitive function.

Hormone replacement therapy (HRT)—more specifically estrogen replacementtherapy (ERT)—is commonly prescribed to address the medical problemsassociated with menopause, and also to help hinder osteoporosis andprimary cardiovascular complications (such as coronary artery disease)in both a preventive and therapeutical manner. As such, HRT isconsidered a medical therapy for prolonging the average life span ofpostmenopausal women and providing a better quality of life.

ERT effectively relieves the climacteric symptoms and urogenitalsymptoms and has shown some benefits in the prevention and treatment ofheart disease in postmenopausal women. Clinical reports have shown thatERT lowered heart attack rates and mortality rates in populations thatreceived ERT versus similar populations not on ERT. ERT initiated soonafter menopause may also help maintain bone mass for several years.Controlled investigations have shown that treatment with ERT has apositive effect even in older women up to 75 years of age.

However, there are numerous undesirable effects associated with ERT thatreduce patient compliance. Venous thromboembolism, gallbladder disease,resumption of menses, mastodynia, and a possible increased risk ofdeveloping uterine and/or breast cancer are the risks associated withERT. Up to 30% of women who are prescribed ERT do not fill theprescription, and the discontinuation rate for ERT is between 38% and70%, with safety concerns, and adverse effects (bloating andbreak-through bleeding) the most important reasons for discontinuation.

A new class of pharmacological agents known as Selective EstrogenReceptor Modulators or SERMs have been designed and developed asalternatives for HRT. Raloxifene, a nonsteroidal benzothiophere SERM ismarketed in the US and Europe for the prevention and treatment ofosteoporosis under the trademark of Evista®. Raloxifene has been shownto reduce bone loss and prevent fracture without adversely stimulatingendometrial and mammary tissue, though raloxifene is somewhat lessefficacious than ERT for protecting against bone loss. Raloxifene isunique and differs significantly from ERT in that it does not stimulatethe endometrium and has the potential for preventing breast cancer.Raloxifene has also demonstrated beneficial estrogen agonist effects oncardiovascular risk factors, more specifically through a rapid andsustained decrease in total and low-density lipoprotein cholesterollevels in patients treated with raloxifene. In addition, raloxifene hasbeen shown to reduce plasma concentration of homocysteine, anindependent risk factor for atherosclerosis and thromboembolic disease.

However, raloxifene has been reported to exacerbate symptoms associatedwith menopause such as hot flushes and vaginal dryness, and does notimprove cognitive function in senior patients. Patients takingraloxifene have reported higher rates of hot flashes compared witheither placebo or ERT users and more leg cramps than placebo users,although women who took ERT had a higher incidence of vaginal bleedingand breast discomfort than raloxifene or placebo users.

As yet, neither raloxifene nor any of the other currently available SERMcompounds has been shown to have the ability to provide all the benefitsof currently available ERT, such as controlling postmenopausal syndromeand preventing AD, without causing adverse side effects such asincreasing risk of endometrial and breast cancer and bleeding. Thusthere exists a need for compounds which are selective estrogen receptormodulators and which provide all of the benefits of ERT while alsoaddressing the vasomotor, urogenital and cognitive disorders orconditions associated with the decrease in systemic estrogen associatedwith menopause.

Androgens are the anabolic steroid hormones of animals, controllingmuscle and skeletal mass, the maturation of the reproductive system, thedevelopment of secondary sexual characteristics and the maintenance offertility in the male. In women, testosterone is converted to estrogenin most target tissues, but androgens themselves may play a role innormal female physiology, for example, in the brain. The chief androgenfound in serum is testosterone, and this is the effective compound intissues such as the testes and pituitary. In prostate and skin,testosterone is converted to dihydrotestosterone (DHT) by the action of5α-reductase. DHT is a more potent androgen than testosterone because itbinds more strongly to the androgen receptor.

Like all steroid hormones, androgens bind to a specific receptor insidethe cells of target tissues, in this case the androgen receptor. This isa member of the nuclear receptor transcription factor family. Binding ofandrogen to the receptor activates it and causes it to bind to DNAbinding sites adjacent to target genes. From there it interacts withcoactivator proteins and basic transcription factors to regulate theexpression of the gene. Thus, via its receptor, androgens cause changesin gene expression in cells. These changes ultimately have consequenceson the metabolic output, differentiation or proliferation of the cellthat are visible in the physiology of the target tissue.

Although modulators of androgen receptor function have been employedclinically for some time, both the steroidal (Basaria, S., Wahlstrom, J.T., Dobs, A. S., J. Clin Endocrinol Metab (2001), 86, pp 5108-5117;Shahidi, N. T., Clin Therapeutics, (2001), 23, pp 1355-1390), andnon-steroidal (Newling, D. W., Br. J. Urol., 1996, 77 (6), pp 776-784)compounds have significant liabilities related to their pharmacologicalparameters, including gynecomastia, breast tenderness and hepatoxicity.In addition, drug-drug interactions have been observed in patientsreceiving anticoagulation therapy using coumarins. Finally, patientswith aniline sensitivities could be compromised by the metabolites ofnon-steroidal antiandrogens.

Non-steroidal agonists and antagonists of the androgen receptor areuseful in the treatment of a variety of disorders and diseases. Moreparticularly, agonists of the androgen receptor could be employed in thetreatment of prostate cancer, benign prostatic hyperplasia, hirsutism inwomen, alopecia, anorexia nervosa, breast cancer and acne. Antagonistsof the androgen receptor could be employed in male contraception, maleperformance enhancement, as well as in the treatment of cancer, AIDS,cachexia, and other disorders.

Progesterone plays a major role in reproductive health and functioning.Its effects on, for example, the uterus, breast, cervix andhypothalamic-pituitary unit are well established. The actions ofprogesterone as well as progesterone antagonists are mediated by theprogesterone receptor (PR). In the target cell, progesterone produces adramatic change in confirmation of the PR that is associated withtransforming the PR from a non-DNA binding form to one that will bind toDNA. This transformation is accompanied by a loss of associated heatshock proteins and dimerization. The activated PR dimmer then binds tospecific DNA sequences within the promotor region of progesteroneresponsive genes. The agonist-bound PR is believed to activatetranscription by associating with coactivators, which act as bridgingfactors between the receptor and the general transcription machinery.This is followed by increases in the rate of transcription producingagonist effects at the cellular and tissue levels. These progesteronereceptor ligands exhibit a spectrum of activity ranging from pureantagonists to mixed agonists/antagonists.

In 1982, the discovery of compounds that bind to the progesteronereceptor, antagonize the effects of progesterone receptor and antagonizethe effects of progesterone was announced. Although compounds such asestrogens and certain enzyme inhibitors can prevent the physiologicaleffects of endogenous progesterone, the term “antiprogestin” is confinedto those compounds that bind to the progestin receptor. A report fromthe Institute of Medicine (Donaldson, Molly S.; Dorflinger, L.; Brown,Sarah S.; Benet, Leslie Z., Editors, Clinical Applications ofMifepristone (RU 486) and Other antiprogestins, Committee onantiprogestins: Assessing the science, Institute of medicine, NationalAcademy Press, 1993) summarized a number of medical conditions relatedto the effect of antiprogestins. In view of the pivotal role thatprogesterone plays in reproduction, it is not surprising thatantiprogestins could play a part in fertility control, includingcontraception, menses induction and medical termination of pregnancy,but there are many other potential uses that have been supported bysmall clinical or preclinical studies, such as labor and delivery;treatment of uterine leiomyomas (fibroids), treatment of endometriosis;HRT; breast cancers; male contraception, etc.

The effects and uses of progesterone agonists have been wellestablished. In addition, it has been recently shown that certaincompounds structurally related to the known antiprogestins have agonistactivity in certain biological systems (e.g., the classical progestineffects I the estrogen-primed immature rabbit uterus; cf. C. E. Cook etal., Life Sciences, 52, 155-162 (1993)). Such compounds are partialagonists in human cell-derived receptor systems, where they bind to asite distinct from both the progestin and antiprogestin sites (Wagner etal., Proc. Natl. Acad. Sci., 93, 8739-8744 (1996)). Thus the generalclass of antiprogestins can have subclasses, which may vary in theirclinical profiles.

Compounds which mimic some of the effects of progesterone (agonists),antagonize these effects (antagonists, antiprogestins) or exhibit mixedeffects (partial agonists or mixed agonist/antagonist), known asprogesterone receptor modulators (PRMs) can be useful in treating avariety of disease states and conditions. PR agonists have been used infemale contraceptives and in postmenopausal hormone therapy. Recentstudies in women and non-human primates show that PR antagonists mayalso have potential as contraceptive agents and for the treatment ofvarious gynecological and obstetric diseases, including fibroids,endometriosis and, possibly, hormone-dependent cancers. Clinicallyavailable PR agonists and antagonists are steroidal compounds and oftencause various side effects due to their functional interaction withother steroid receptors. Recently, numerous receptor-selectivenon-steroidal PR agonists and antagonists have emerged. Non-steroidal PRantagonists, being structurally distinct from the steroid class, mayhave greater potential for selectivity against other steroid receptors.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of formula (I)

wherein

X is selected from the group consisting of —O—, —S and NR^(A)— whereinR^(A) is selected from the group consisting of hydrogen, C₁₋₆alkyl,—C(O)—C₁₋₆alkyl, —C₁₋₄alkyl-NR^(C)R^(D) and -L¹-R⁴-(L²)_(c)-R⁵;

R¹ is selected from the group consisting of hydrogen, hydroxy,C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, —C₁₋₄alkyl-NR^(C)R^(D) and-L¹-R⁴-(L²)_(c)-R⁵;

is a five to seven membered aromatic, partially unsaturated or saturatedring structure, optionally containing one to two heteroatomsindependently selected from O, N or S; wherein the heteroatom(s) are notthe bridge atom(s);

a is an integer selected from 0 to 2;

R² is selected from the group consisting of halogen, hydroxy, carboxy,oxo, cyano, nitro, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkyl,C₁₋₄alkoxy, halogenated C₁₋₄alkyl, —O-aralkyl, —C(O)—C₁₋₄alkyl,—C(O)O—C₁₋₄alkyl, —OC(O)—C₁₋₄alkyl, —O—SO₂—C₁₋₄alkyl, —O—SO₂—(halogenated C₁₋₄alkyl) and —O—Si(CH₃)₂(t-butyl);

b is an integer selected from 0 to 2;

R³ is selected from the group consisting of halogen, hydroxy, carboxy,oxo, cyano, nitro, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkyl,C₁₋₄alkoxy, halogenated C₁₋₄alkyl, —O-aralkyl, —C(O)—C₁₋₄alkyl,—C(O)O—C₁₋₄alkyl, —OC(O)—C₁₋₄alkyl, —O—SO₂—C₁₋₄alkyl, —O—SO₂—(halogenated C₁₋₄alkyl) and —O—Si(CH₃)₂(t-butyl);

L¹ is selected from the group consisting of —CH₂— and —C(O)—;

R⁴ is selected from the group consisting of a five to six membered aryland a five to six membered heteroaryl;

c is an integer selected from 0 to 1;

L² is selected from the group consisting of —C₁₋₄alkyl-, —C₂₋₄alkenyl-,—O—C₁₋₃alkyl-, —S—C₁₋₄alkyl- and —NR^(B)—C₁₋₃alkyl-; wherein R^(B) isselected from hydrogen or C₁₋₄alkyl;

R⁵ is selected from the group consisting of —NR^(C)R^(D),—C(O)—C₁₋₄alkyl, —CO₂H, —C(O)O—C₁₋₄alkyl and —OC(O)—C₁₋₄alkyl;

wherein R^(C) and R^(D) are independently selected from hydrogen orC₁₋₄alkyl; alternatively, R^(C) and R^(D) are taken together with thenitrogen atom to which they are bound to form a five to seven memberedaromatic, partially aromatic or saturated ring structure; wherein thering structure optionally contains one to two additional heteroatomsselected from O, N or S;

provided further that R^(A) and R¹ are not each -L¹-R⁴-(L²)_(c)-R⁵;

provided further that when a is 0 and b is 0; then one of R^(A) or R¹ is-L¹-R⁴-(L²)_(c)-R⁵;

provided further that when R¹ is hydrogen; and

is phenyl; then at least one of a or b is other than 0;

provided further that when X is —NH— or —N(C₁₋₆alkyl)-; R¹ is hydrogenor C₁₋₆alkyl; a is 0 to 1; R² is halogen or —C(O)O—C₁₋₄alkyl; b is 1;and R³ is halogen or —C(O)O—C₁₋₄alkyl; then

is other than phenyl;

provided further that when X is —O—; R¹ is hydrogen or C₁₋₄alkyl;

is phenyl; a is 0 to 1; b is 0 to 1; and at least one of a or b is 1;then at least one of R² or R³ is other than halogen, cyano, nitro,carboxy or —C(O)O—C₁₋₄alkyl;

provided further that when X is —O—;

is phenyl; a is 0; and b is 0; then R¹ is other than—C₁₋₄alkyl-N(C₁₋₄alkyl)₂ or —C₁₋₄alkyl-piperidinyl;

provided further that when X is —O—; R¹ is hydrogen;

is pyridyl or thienyl; a is 0; and b is 1 to 2; then R² is other thanoxo, halogen or —C(O)O—C₁₋₄alkyl;

provided further that when X is —O—; R¹ is hydrogen or C₁₋₄alkyl;

is pyrrolyl; a is 0; and b is 1 or 2; then R² is other than C₁₋₄alkyl or—C(O)O—C₁₋₄alkyl;

provided further that when X is —S—; R¹ is hydrogen, C₁₋₄alkyl,—C₁₋₄alkyl-N(C₁₋₄alkyl)₂, —C₁₋₄alkyl-piperidinyl,—C₁₋₄alkyl-pyrrolidinyl or —C₁₋₄alkyl-morpholinyl;

is phenyl; a is 0 to 2; and b is 0 to 2; then at least one of R² or R³is other than halogen, C₁₋₄alkyl, C₁₋₄alkoxy, cyano, nitro, amino or—C(O)O—C₁₋₄alkyl;

or a pharmaceutically acceptable salt thereof.

The present invention is further directed to compounds of formula (II)

wherein

Y is selected from the group consisting of —O—, —S—, —SO—, —SO₂—, —N═,—NH— and —N(CH₃)—; and Z is selected from the group consisting of —CH₂—,—CH(CH₃)—, —C(CH₃)₂— and —CH(OH)—;

alternatively, Y is —CH₂—; and Z is selected from the group consistingof —O—, —S—, —SO— and —SO₂—;

alternatively, Y is —CH═; and Z is selected from the group consisting of—CH₂—, —O—, —S—, —SO— and —SO₂—;

alternatively, Y is selected from the group consisting of —CH₂—, —O—,—S—. —SO— and —SO₂—; and Z is selected from the group consisting of—CH₂CH₂— and —CH═CH—;

represents an optional double bond;

R¹ is selected from the group consisting of hydrogen, hydroxy,C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, —C₁₋₄alkyl-NR^(C)R^(D) and-L¹-R⁴-(L²)_(c)-R⁵;

is a five to seven membered aromatic, partially unsaturated or saturatedring structure, optionally containing one to two heteroatomsindependently selected from O, N or S; wherein the heteroatom(s) are notthe bridge atom(s);

R⁶ is selected from the group consisting of hydrogen, C₁₋₄alkyl and CF₃;

a is an integer selected from 0 to 2;

R² is selected from the group consisting of halogen, hydroxy, carboxy,oxo, cyano, nitro, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkyl,C₁₋₄alkoxy, halogenated C₁₋₄alkyl, —O-aralkyl, —C(O)—C₁₋₄alkyl,—C(O)O—C₁₋₄alkyl, —OC(O)—C₁₋₄alkyl, —O—SO₂—C₁₋₄alkyl,—O—SO₂-(halogenated C₁₋₄alkyl) and —O—Si(CH₃)₂(t-butyl);

b is an integer selected from 0 to 2;

R³ is selected from the group consisting of halogen, hydroxy, carboxy,oxo, cyano, nitro, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkyl,C₁₋₄alkoxy, halogenated C₁₋₄alkyl, —O-aralkyl, —C(O)—C₁₋₄alkyl,—C(O)O—C₁₋₄alkyl, —OC(O)—C₁₋₄alkyl, —O—SO₂—C₁₋₄alkyl, —O—SO₂—(halogenated C₁₋₄alkyl) and —O—Si(CH₃)₂(t-butyl);

L¹ is selected from the group consisting of —CH₂— and —C(O)—;

R⁴ is selected from the group consisting of a five to six membered aryland a five to six membered heteroaryl;

c is an integer selected from 0 to 1;

L² is selected from the group consisting of —C₁₋₄alkyl-, —C₂₋₄alkenyl-,—O—C₁₋₃alkyl-, —S—C₁₋₄alkyl- and —NR^(B)—C₁₋₃alkyl-; wherein R^(B) isselected from hydrogen or C₁₋₄alkyl;

R⁵ is selected from the group consisting of —NR^(C)R^(D),—C(O)—C₁₋₄alkyl, —CO₂H, —C(O)O—C₁₋₄alkyl and —OC(O)—C₁₋₄alkyl;

wherein R^(C) and R^(D) are independently selected from hydrogen orC₁₋₄alkyl; alternatively, R^(C) and R^(D) are taken together with thenitrogen atom to which they are bound to form a five to seven memberedaromatic, partially aromatic or saturated ring structure; wherein thering structure optionally contains one to two additional heteroatomsselected from O, N or S;

provided that when R¹ is hydrogen or methyl; R⁶ is hydrogen; and

is phenyl, pyridyl or thienyl; then at least one of a or b is other than0;

provided further that when Y is —NH—; Z is —CH₂—; R¹ is hydrogen, R⁶ ishydrogen, a is 1, R² is methyl; b is 0 to 1; and R³ is halogen ormethoxy; then

is other than 2-pyridyl;

provided further that when Y is —N(CH₃)—; Z is —C(CH₃)₂—; R¹ is methyl,R⁶ is hydrogen; a is 0; b is 1; and R³ is hydroxy; then

is other than phenyl;

provided further that when Y is —CH₂—; Z is —O—; R⁶ is hydrogen; a is 0;b is 0; and

is phenyl; then R¹ is other than C₁₋₄alkyl or —C(O)—C₁₋₃alkyl;

provided further that when Y is —CH₂—; Z is —O—; R¹ is hydrogen; R⁶ ishydrogen;

is phenyl; a is 1; and b is 0; then R² is other than halogen, nitro orC₁₋₄alkoxy;

provided further that when Y is —CH₂—; Z is —CH₂CH₂—; R¹ is hydrogen, R⁶is hydrogen,

is phenyl; a is 1; and b is 0; then R² is other than halogen;

provided further that when Y is —CH₂—; Z is —CH₂CH₂—; R¹ is hydrogen, R⁶is hydrogen;

is pyrazolyl; a is 1; and b is 0; then R² is other than C₁₋₄alkoxy;

provided further that when Y is —CH₂—; Z is —CH₂CH₂—; R¹ is hydrogen, R⁶is hydrogen;

is thienyl; a is 0; and b is 1; then R³ is other than C₁₋₄alkyl;

provided further that when Y is —CH₂—; Z is —CH₂CH₂—; R¹ is hydrogen orC₁₋₄alkyl-N(C₁₋₄alkyl)₂; R⁶ is hydrogen;

is phenyl; a is 1; R² is nitro; and b is 2; then at least one R³ isother than C₁₋₄alkoxy;

provided further that when Y is —O—; Z is —CH₂CH₂—; R¹ is hydrogen; R⁶is hydrogen; a is 1; R² is methyl; b is 1; and R³ is methyl; then

is other than phenyl;

provided further that when Y is —O—; Z is —CH₂CH₂—; R¹ is hydrogen; R⁶is hydrogen;

is phenyl; a is o to 1; and b is 0; then R² is other than halogen,nitro, amino, —C₁₋₄alkoxy or —C(O)O—C₁₋₄alkyl;

provided further that when Y is —O—; Z is —CH₂CH₂—; R⁶ is hydrogen;

is phenyl; a is 1; R² is methyl; and b is 0; then R¹ is other than—C₁₋₄alkyl-N(CH₃)₂ or —C₁₋₄alkyl-(4-methyl-piperidinyl);

provided further that when Y is —S—, —SO— or —SO₂—; Z is —CH₂CH₂—; R¹ ishydrogen or C₁₋₄alkyl; R⁶ is hydrogen is phenyl;

is 1; and b is 0; then R² is other than C₁₋₄alkyl, carboxy or—C(O)O—C₁₋₄alkyl;

provided further that when Y is —S—; Z is —CH₂CH₂; R⁶ is hydrogen;

is phenyl; a is 0; and b is 0; then R¹ is other than —C₁₋₄alkyl-N(CH₃)₂;

provided further that when Y is —O—; Z is —CH₂—; R¹ is hydrogen; R⁶ ishydrogen;

is phenyl; a is 1; b is 0; then R² is other than C₁₋₄alkyl orC₁₋₄alkoxy;

provided further that when Y is —O—; Z is —CH₂—; R¹ is C₁₋₄alkyl; R⁶ ishydrogen;

is phenyl; a is 1; b is 0; then R² is other than —C(O)O—C₁₋₄alkyl;

provided further that when Y is —O—; Z is —CH₂—; R¹ is hydrogen; R⁶ ishydrogen;

is phenyl; a is 0; b is 1; then R³ is other than halogen or C₁₋₄alkyl;

provided further that when Y is —O—; Z is —CH₂—; R⁶ is hydrogen;

is phenyl; a is 0; and b is 0; then R¹ is other than —C₁₋₄alkyl-N(CH₃)₂;

provided further that when Y is —S—; Z is —C(CH₃)₂—; R¹ is hydrogen; R⁶is hydrogen,

is phenyl; a is 0; and b is 1; then R³ is other than halogen;

provided further that when Y is —S—; Z is —CH₂—; R¹ is hydrogen; R⁶ ishydrogen;

is phenyl; a is 1; and b is 0; then R² is other than halogen, C₁₋₄alkyl,C₁₋₄alkoxy, carboxy, trifluoromethyl or —C(O)O—C₁₋₄alkyl;

provided further that when Y is —S—; Z is —CH₂—; R¹ is hydrogen; R⁶ ishydrogen;

is phenyl; a is 2; and b is O; then the two R² groups are selected to beother than (halogen and C₁₋₄alkyl), (hydroxy and C₁₋₄alkyl), (C₁₋₄alkyland C₁₋₄alkyl), (C₁₋₄alkyl and C₁₋₄alkoxy) or (halogen and halogen);

provided further than when Y is —S—, —SO— or —SO₂—; Z is —CH₂—; R¹ ishydrogen; R⁶ is hydrogen;

is phenyl; a is 0; and b is 1; then R³ is other than halogen, C₁₋₄alkyl,C₁₋₄alkoxy, trifluoromethyl, nitro or amino;

provided further than when Y is —S—; Z is —CH₂—; R¹ is hydrogen; R⁶ ishydrogen;

is phenyl; a is 1; R² is C₁₋₄alkyl or halogen; and b is 1; then R³ isother than halogen or C₁₋₄alkyl;

provided further than when Y is —S—; Z is —CH₂—; R¹ is hydrogen; R⁶ ishydrogen;

is phenyl; a is 1; R² is —C(O)O—C₁₋₄alkyl; and b is 1; then R³ is otherthan C₁₋₄alkyl;

provided further that when Y is —SO₂—; Z is —CH₂—; R¹ is hydrogen; R⁶ ishydrogen;

is phenyl; a is 1; and b is 0; then R² is other than carboxy, C₁₋₄alkoxyor —C(O)O—C₁₋₄alkyl;

provided further that when Y is —S—, —SO— or —SO₂—; Z is —CH₂—; R¹ isC₁₋₄alkyl; R⁶ is hydrogen,

is phenyl; a is 1; and b is 0; then R² is other than carboxy or—C(O)O—C₁₋₄alkyl;

provided further that when Y is —S—, —SO— or —SO₂—; Z is —CH₂—; R⁶ ishydrogen;

is phenyl, a is 0; and b is 0; then R¹ is other than —C₁₋₄alkyl-N(CH₃)₂;

provided further that when Y is —S—; Z—CH₂—; R¹ is hydrogen; R⁶ ishydrogen; a is 1; R² is halogen or C₁₋₄alkoxy; b is 1; and R³ isC₁₋₄alkyl; then

is other than cyclopentyl or 2-pyridyl;

provided further that when Y is —S—; Z—CH₂—; R¹ is hydrogen; R⁶ ishydrogen; a is 0; b is 1; and R³ is C₁₋₄alkyl; then

is other than 2-pyridyl;

provided further that when Y is —S—; Z—CH₂—; R¹ is hydrogen; R⁶ ishydrogen; a is 1; R² is halogen or C₁₋₄alkoxy; then

is other than 2-pyridyl;

provided further that when Y is —S—; Z—CH₂—; R¹ is hydrogen; R⁶ ishydrogen; a is 0; b is 2; and each R³ is C₁₋₄alkyl; then

is other than 2-thienyl;

provided further that when Y is —S—; Z is —C(CH₃)₂—; R¹ is hydrogen; R⁶is hydrogen; a is 0; b is 2; one R³ is C₁₋₄alkyl and the other R³ isoxo; then

is other than 3-pyrrolidinyl;

or a pharmaceutically acceptable salt thereof.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and any of the compounds describedabove. An illustration of the invention is a pharmaceutical compositionmade by mixing any of the compounds described above and apharmaceutically acceptable carrier. Illustrating the invention is aprocess for making a pharmaceutical composition comprising mixing any ofthe compounds described above and a pharmaceutically acceptable carrier.

Exemplifying the invention are methods of treating a disorder mediatedby one or more sex steroid hormone receptors, in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of any of the compounds or pharmaceutical compositionsdescribed above.

Further exemplifying the invention are methods of treating a disordermediated by one or more estrogen, androgen or progestin receptors, in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of any of the compounds orpharmaceutical compositions described above.

An example of the invention is a method for treating a disorder orcondition selected from the group consisting of hot flashes, vaginaldryness, osteopenia, osteoporosis, hyperlipidemia, loss of cognitivefunction, degenerative brain diseases, cardiovascular diseases,cerebrovascular diseases, hormone sensitive cancers and hyperplasia (intissues including breast, endometrium, and cervix in women and prostatein men), endometriosis, uterine fibroids, osteoarthritis, prostatecarcinoma, benign prostatic hyperplasia (BPH), hirsitutism, alopecia,anorexia nervosa, breast cancer, acne, AIDS, cachexia, endometriosis(preferably, without associated bone loss and/or hypoestrogenism), myoma(preferably, without associated bone loss and/or hypoestrogenism),dysfunctional bleeding, tumors containing steroid receptors, malecontraception, female contraception, male performance enhancement, andhormone replacement, in a subject in need thereof, comprisingadministering to the subject an effective amount of any of the compoundsor pharmaceutical compositions described above.

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament for treating: (a)hot flashes, (b) vaginal dryness, (c) osteopenia, (d) osteoporosis, (e)hyperlipidemia, (f) loss of cognitive function, (g) degenerative braindiseases, (h) cardiovascular diseases, (i) cerebrovascular diseases, (j)hormone sensitive cancers, (k) hormone sensitive hyperplasia, (l)endometriosis, (m) uterine fibroids, (n) osteoarthritis, (o) prostatecarcinoma, (p) benign prostatic hyperplasia, (q) hirsitutism, (r)alopecia, (s) anorexia nervosa, (t) breast cancer, (u) acne, (v) AIDS,(w) cachexia, (x) endometriosis, (y) myoma, (z) dysfunctional bleeding,(aa) tumors containing steroid receptors, (bb) for male contraception,(cc) for female contraception, (dd) for male performance enhancement or(dd) for hormone replacement in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of formula (I) andcompounds of formula (II)

wherein X, Y, Z, a, b, R¹, R², R³, R⁶,

and

as herein defined, useful for the treatment and/or prevention ofdisorders or conditions mediated by one or more sex steroid hormonereceptors, more particularly, one or more estrogen, androgen and/orprogestin receptors.

In an embodiment, the compounds of the present invention are useful forthe treatment of estrogen receptor modulated disorders. In anotherembodiment, the compounds of the present invention are useful for thetreatment of disorders mediated by the estrogen-α and/or estrogen-βreceptor. In yet another embodiment, the compounds of the presentinvention are useful for the treatment of an estrogen mediated disorderselected from the group consisting of the treatment and/or prevention ofdisorders associated with the depletion of estrogen, hormone sensitivecancers and hyperplasia, endometriosis, uterine fibroids, osteoarthritisand as contraceptive agents, alone or in combination with a progestogenor progestogen antagonist.

More particularly, the compounds of the present invention are useful forthe treatment and/or prevention of a condition or disorder selected fromthe group consisting of hot flashes, vaginal dryness, osteopenia,osteoporosis, hyperlipidemia, loss of cognitive function, degenerativebrain diseases, cardiovascular diseases, cerebrovascular diseases,cancer or hyperplasia of the breast tissue, cancer or hyperplasia of theendometrium, cancer or hyperplasia of the cervix, cancer or hyperplasiaof the prostate, endometriosis, uterine fibroids and osteoarthritis; andas a contraceptive agent. Preferably, the disorder is selected from thegroup consisting of osteoporosis, hot flashes, vaginal dryness, breastcancer, and endometriosis.

In an embodiment, the compounds of the present invention are useful forthe treatment of androgen receptor modulated disorders. In anotherembodiment, the compounds of the present invention are useful for thetreatment of an androgen receptor modulated disorder selected from thegroup consisting of prostate carcinoma, benign prostatic hyperplasia,hirsutism, or for male contraception. In yet another embodiment, thecompounds of the present invention are useful for the treatment ofprostate carcinoma, benign prostatic hyperplasia, hirsutism, alopecia,anorexia nervosa, breast cancer, acne, AIDS, cachexia, for malecontraception, and/or for male performance enhancement.

In an embodiment, the compounds of the present invention are useful inthe treatment of progestin modulated disorders. More particularly, thecompounds of the present invention are useful as contraceptives, for thetreatment of endometriosis (preferably without associated bone lossand/or hypoestrogenism), myoma (preferably, without associated bone lossand/or hypoestrogenism), dysfunctional bleeding, tumors containingsteroid receptors and/or as an adjunct to estrogens in hormonereplacement therapy.

In an embodiment of the present invention are compounds of formula (I)which are useful in the treatment of estrogen receptor modulateddisorders and diseases. In an embodiment of the present invention arecompounds of formula (II) which are useful in the treatment of estrogenreceptor modulated disorders and diseases.

In an embodiment of the present invention are compounds of formula (I)which are useful in the treatment of androgen receptor modulateddisorders and diseases. In an embodiment of the present invention arecompounds of formula (II) which are useful in the treatment of androgenreceptor modulated disorders and diseases.

In an embodiment of the present invention are compounds of formula (I)which are useful in the treatment of progestin receptor modulateddisorders and diseases. In an embodiment of the present invention arecompounds of formula (I) which are useful in the treatment of progestinreceptor modulated disorders and diseases.

In an embodiment of the present invention Y is selected from the groupconsisting of —O—, —S—, —SO— and —SO₂—; and Z is selected from the groupconsisting of —CH₂—, —CH(CH₃)—, C(CH₃)₂— and —CH(OH)—. In anotherembodiment of the present invention Y is selected from the groupconsisting of —N═, —NH— and —N(CH₃)—; and Z is selected from the groupconsisting of —CH₂—, —CH(CH₃)—, C(CH₃)₂— and —CH(OH)—.

In an embodiment of the present invention Y is —CH₂—; and Z is selectedfrom the group consisting of —O—, —S—, —SO— and —SO—. In anotherembodiment of the present invention, Y is —CH═; and Z is of —CH₂—. Inyet another embodiment of the present invention, Y is —CH═; and Z isselected from the group consisting of —O—, —S—, —SO— and —SO₂—.

In an embodiment of the present invention Y is —CH₂—; and Z is selectedfrom the group consisting of —CH₂CH₂— and —CH═CH—. In another embodimentof the present invention, Y is selected from the group consisting of—O—, —S—. —SO— and —SO₂; and Z is selected from the group consisting of—CH₂CH₂— and —CH═CH—.

In an embodiment of the present invention Y is selected from the groupconsisting of —O—, —S—, —SO—, —SO₂—, —NH— and —N(CH₃)—; and Z isselected from the group consisting of —CH₂—, —C(CH₃)₂— and —CH(OH)—.

In an embodiment of the present invention, Y is —CH₂—; and Z is selectedfrom the group consisting of —S—, —SO— and —SO₂—. In another embodimentof the present invention, Y is —CH₂—; and Z is —S—.

In an embodiment of the present invention, Y is —CH═; and Z is —CH₂—.

In an embodiment of the present invention, Y is selected from the groupconsisting of —CH₂—, —S—, —SO— and —SO₂—; and Z is selected from thegroup consisting of —CH₂CH₂— and —CH═CH—. In another embodiment of thepresent invention, Y is selected from the group consisting of —CH₂—, —S—and —SO—; and Z is selected from the group consisting of —CH₂CH₂— and—CH═CH—.

In an embodiment of the present invention X is O.

In an embodiment of the present invention a is an integer from 0 to 1.In another embodiment of the present invention b is and integer from 0to 1. In yet another embodiment of the present invention a is 1 and bis 1. In yet another embodiment of the present invention c is 1.

In an embodiment of the present invention R¹ is selected from the groupconsisting of hydrogen and -L¹-R⁴-(L²)_(c)-R⁵. Preferably, R¹ isselected from the group consisting of hydrogen and—CH₂-phenyl-O—C₁₋₃alkyl-NR^(B)R^(C). More preferably, R¹ is selectedfrom the group consisting of hydrogen and4-(diethylamino-ethoxy)-benzyl.

In an embodiment of the present invention, R¹ is selected from the groupconsisting of hydrogen, hydroxy, C₁₋₄alkyl, —C(O)—C₁₋₄alkyl,—C₁₋₄alkyl-NR^(C)R^(D) and -L¹-R⁴-(L²)_(c)-R⁵. In another embodiment ofthe present invention, R¹ is selected from the group consisting ofhydrogen, hydroxy, methyl, ethyl, methylcarbonyl-, dimethylamino-ethyl,4-(diethylamino-ethoxy)-benzyl, 4-(piperidinyl-ethoxy)-benzyl,4-(pyrrolidinyl-ethoxy)-benzyl, 4-(piperidinyl-ethoxy)-phenyl-carbonyland 4-(methyl-carbonyloxy)-phenyl-carbonyl.

In an embodiment of the present invention, R¹ is selected from the groupconsisting of hydrogen, hydroxy, C₁₋₄alkyl, —C(O)—C₁₋₄alkyl,—C₁₋₄alkyl-NR^(C)R^(D) and -L¹-R⁴-(L²)_(c)-R⁵. In another embodiment ofthe present invention, R¹ is selected from the group consisting ofhydrogen, hydroxy, methyl, ethyl, methylcarbonyl-, dimethylamino-ethyl,4-(diethylamino-ethoxy)-benzyl, 4-(piperidinyl-ethoxy)-benzyl,4-(piperidinyl-ethoxy)-phenyl-carbonyl and4-(methyl-carbonyloxy)-phenyl-carbonyl.

In an embodiment of the present invention, R¹ is selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and -L¹-R⁴-(L²)_(c)-R⁵. In anotherembodiment of the present invention, R¹ is selected from the groupconsisting of hydrogen, methyl, 4-(piperidinyl-ethoxy)-benzyl and4-(pyrrolidinyl-ethoxy)-benzyl.

In an embodiment of the present invention, R¹ is selected from the groupconsisting of hydrogen, hydroxy, C₁₋₆alkyl, —C(O)—C₁₋₆alkyl,—C₁₋₄alkyl-NR^(C)R^(D) and -L¹-R⁴-(L²)_(c)-R⁵. In another embodiment ofthe present invention, R¹ is selected from the group consisting ofhydrogen, hydroxy, C₁₋₄alkyl, —C(O)—C₁₋₄alkyl, —C₁₋₄alkyl-NR^(C)R^(D)and -L¹-R⁴-(L²)_(c)-R⁵. In another embodiment of the present invention,R¹ is selected from the group consisting of hydrogen, hydroxy, methyl,ethyl, methylcarbonyl-, diethylamino-ethyl-,4-(piperidinyl-ethoxy)-benzyl-, 4-(pyrrolidinyl-ethoxy)-benzyl-,4-(diethylamino-ethoxy)-benzyl-, 4-(piperidinyl-ethoxy)-phenyl-carbonyl-and 4-(methyl-carbonyloxy)-phenyl-carbonyl.

In an embodiment of the present invention, R¹ is selected from the groupconsisting of hydrogen, C₁₋₂alkyl and -L¹-R⁴-(L²)_(c)-R⁵. In anotherembodiment of the present invention, R¹ is selected from the groupconsisting of —C₁₋₄alkyl-NR^(C)R^(D) and -L¹-R⁴-(L²)_(c)-R⁵. In anotherembodiment of the present invention, R¹ is -L¹-R⁴-(L₂)_(c)-R⁵. In yetanother embodiment of the present invention, R¹ is—C₁₋₄alkyl-NR^(C)R^(D).

In an embodiment of the present invention, when R¹ is other thanC₁₋₆alkyl. In another embodiment of the present invention, R¹ is otherthan hydrogen of C₁₋₆alkyl.

In an embodiment of the present invention,

a five to six membered aromatic, partially unsaturated or saturated ringstructure, optionally containing one to two heteroatoms independentlyselected from O or N; wherein the heteroatom(s) are not the bridgeatom(s). In another embodiment of the present invention,

is a five to six membered aromatic ring structure, optionally containingone to two heteroatoms independently selected from O or N; wherein theheteroatom(s) are not the bridge atom(s). In another embodiment of thepresent invention

is a six membered aromatic, partially unsaturated or saturated ringstructure, optionally containing one to two heteroatoms independentlyselected from O, N or S; wherein the heteroatom(s) are not the bridgeatom(s). In another embodiment of the present invention

is a six membered aromatic or saturated ring structure, optionallycontaining one to two heteroatoms independently selected from O, N or S;wherein the heteroatom(s) are not the bridge atom(s). In anotherembodiment of the present invention

is phenyl. In yet another embodiment of the present invention

selected from the group consisting of phenyl, pyrrolyl, thienyl,pyridyl, pyrazinyl, pyrazolyl, piperidinyl and cyclohexen-1-yl (i.e.

In yet another embodiment of the present invention,

is selected from the group consisting of phenyl, 2-pyridyl andpiperidinyl.

In an embodiment of the present invention R⁶ is selected from the groupconsisting of hydrogen and C₁₋₃alkyl. Preferably, R⁶ is selected fromthe group consisting of hydrogen and methyl. In another embodiment ofthe present invention R⁶ is selected from the group consisting ofhydrogen, methyl and CF₃.

In an embodiment of the present invention R² is C₁₋₄alkoxy. Preferably,R² is methoxy.

In an embodiment of the present invention, R² is selected from the groupconsisting of halogen, hydroxy, carboxy, oxo, cyano, nitro, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkoxy, halogenated C₁₋₄alkyl,—C(O)—C₁₋₄alkyl, —C(O)O—C₁₋₄alkyl, —OC(O)—C₁₋₄alkyl, —O—SO₂—C₁₋₄alkyl,—O—SO₂-(halogenated C₁₋₄alkyl) and —O—Si(CH₃)₂(t-butyl).

In an embodiment of the present invention, R² is selected from the groupconsisting of hydroxy, carboxy, halogen, C₁₋₄alkoxy, cyano,—C(O)O—C₁₋₄alkyl, —OC(O)—C₁₋₄alkyl, —O—SO₂—C₁₋₄alkyl,—O—SO₂-(halogenated C₁₋₄alkyl) and —O—Si(CH₃)₂(t-butyl). In anotherembodiment of the present invention, R² is selected from the groupconsisting of hydroxy, carboxy, chloro, fluoro, bromo, methoxy, cyano,methoxy-carbonyl-, methyl-carbonyloxy-, methyl-sulfonyloxy-,trifluoromethyl-sulfonyloxy-,1,1,2,2,3,3,4,4,4-nonafluorobutyl-sulfonyloxy-, t-butyl-carbonyloxy- andt-butyl-dimethyl-silyloxy-.

In an embodiment of the present invention, R² is selected from the groupconsisting of hydroxy, carboxy, halogen, C₁₋₄alkoxy, cyano,—C(O)O—C₁₋₄alkyl, —OC(O)—C₁₋₄alkyl, —O—SO₂—C₁₋₄alkyl, —O—SO₂—(halogenated C₁₋₄alkyl) and —O—Si(CH₃)₂(t-butyl). In another embodimentof the present invention, R² is selected from the group consisting ofhydroxy, carboxy, chloro, fluoro, bromo, methoxy, cyano,methoxy-carbonyl-, methyl-carbonyloxy-, methyl-sulfonyloxy-,trifluoromethyl-sulfonyloxy-,1,1,2,2,3,3,4,4,4-nonafluorobutyl-sulfonyloxy-, t-butyl-carbonyloxy- andt-butyl-dimethyl-silyloxy-.

In an embodiment of the present invention, R² is selected from the groupconsisting of hydroxy and C₁₋₄alkoxy. In another embodiment of thepresent invention, R² is selected from the group consisting of hydroxyand methoxy.

In an embodiment of the present invention, R² is selected from the groupconsisting of halogen, hydroxy, carboxy, cyano, nitro, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkoxy, —O-aralkyl,—C(O)O—C₁₋₄alkyl, —OC(O)—C₁₋₄alkyl, —O—SO₂—C₁₋₄alkyl, —O—SO₂(halogenatedC₁₋₄alkyl) and —O—Si(CH₃)₂(t-butyl). In another embodiment of thepresent invention, R² is selected from the group consisting of halogen,hydroxy, carboxy, cyano, C₁₋₄alkoxy, —C(O)O—C₁₋₄alkyl, —OC(O)—C₁₋₄alkyl,—O—SO₂— (halogenated C₁₋₄alkyl) and —O—Si(CH₃)₂(t-butyl). In anotherembodiment of the present invention, R² is selected from the groupconsisting of hydroxy, carboxy, chloro, fluoro, bromo, methoxy, cyano,methoxy-carbonyl-, methyl-carbonyloxy-, t-butyl-carbonyloxy-,trifluoromethyl-sulfonyloxy-,(1,1,2,2,3,3,4,4,4-nonafluorobutyl)-sulfonyloxy- and(t-butyl-dimethyl-silyloxy)-.

In an embodiment of the present invention, R³ is selected from the groupconsisting of hydroxy and —O-aralkyl. Preferably, R³ is selected fromthe group consisting of hydroxy and benzyloxy.

In an embodiment of the present invention, R³ is selected from the groupconsisting of halogen, hydroxy, carboxy, oxo, cyano, nitro, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkyl, C₁₋₄alkoxy, halogenatedC₁₋₄alkyl, —O-aralkyl, —C(O)—C₁₋₄alkyl, —C(O)O—C₁₋₄alkyl,—OC(O)—C₁₋₄alkyl, —O—SO₂—C₁₋₄alkyl, —O—SO₂— (halogenated C₁₋₄alkyl) and—O—Si(CH₃)₂(t-butyl).

In an embodiment of the present invention, R³ is selected from the groupconsisting of halogen, hydroxy, carboxy, oxo, amino, C₁₋₄alkyl,C₁₋₄alkoxy, halogenated C₁₋₄alkyl, —O-aralkyl and —O—Si(CH₃)₂(t-butyl).In another embodiment of the present invention, R³ is selected from thegroup consisting of hydroxy, carboxy, oxo, bromo, fluoro, methyl,methoxy, trifluoromethyl, benzyloxy, amino andt-butyl-dimethyl-silyloxy-.

In an embodiment of the present invention, R³ is selected from the groupconsisting of halogen, hydroxy, carboxy, oxo, amino, C₁₋₄alkyl,C₁₋₄alkoxy, halogenated C₁₋₄alkyl, —O-aralkyl and —O—Si(CH₃)₂(t-butyl).In another embodiment of the present invention, R³ is selected from thegroup consisting of hydroxy, carboxy, oxo, bromo, fluoro, methyl,methoxy, trifluoromethyl, benzyloxy, amino andt-butyl-dimethyl-silyloxy-.

In an embodiment of the present invention, R³ is selected from the groupconsisting of hydroxy and C₁₋₄alkoxy. In another embodiment of thepresent invention, R³ is selected from the group consisting of hydroxyand methoxy.

In an embodiment of the present invention, R³ is selected from the groupconsisting of halogen, hydroxy, carboxy, oxo, C₁₋₄alkyl, C₁₋₄alkoxy,halogenated C₁₋₄alkyl, —O-aralkyl, —OC(O)—C₁₋₄alkyl, —O—SO₂—C₁₋₄alkyl,—O—SO₂— (halogenated C₁₋₄alkyl) and —O—Si(CH₃)₂(t-butyl). In anotherembodiment of the present invention, R³ is selected from the groupconsisting of halogen, hydroxy, carboxy, oxo, C₁₋₄alkyl, C₁₋₄alkoxy,halogenated C₁₋₄alkyl, —O-aralkyl, and —O—Si(CH₃)₂(t-butyl). In anotherembodiment of the present invention, R³ is selected from the groupconsisting of hydroxy, carboxy, oxo, methyl, methoxy, benzyloxy, bromo,fluoro, trifluoromethyl and (t-butyl-dimethyl-silyloxy)-.

In an embodiment of the present invention, L¹ is —CH₂—.

In an embodiment of the present invention, R⁴ is selected from the groupconsisting of six membered aryl and six membered heteroaryl. In anotherembodiment of the present invention, R⁴ is phenyl.

In an embodiment of the present invention, L² is selected from the groupconsisting of —C₁₋₄alkyl- and —O—C₁₋₃alkyl-. In another embodiment ofthe present invention, L² is —O—C₁₋₃alkyl. In another embodiment of thepresent invention, L² is selected from the group consisting of—O—C₁₋₃alkyl-, —S—C₁₋₃alkyl- and —NR^(B)—C₁₋₃alkyl; wherein R^(B) isselected from hydrogen or C₁₋₄alkyl.

In an embodiment of the present invention, R⁵ is selected from the groupconsisting of —NR^(B)R^(C), —CO₂H and —CO₂—C₁₋₄alkyl. In anotherembodiment of the present invention, R⁵ is selected from the groupconsisting of —CO₂—C₁₋₄alkyl and —NR^(C)R^(D); wherein R^(C) and R^(D)are independently selected from hydrogen or C₁₋₄alkyl; alternatively,R^(C) and R^(D) are taken together with the nitrogen atom to which theyare bound to form a five to seven membered aromatic, partially aromaticor saturated ring structure; wherein the ring structure optionallycontains one to two additional heteroatoms selected from O, N or S.

In an embodiment of the present invention, R⁵ is —NR^(C)R^(D); whereinR^(C) and R^(D) are independently selected from hydrogen or C₁₋₄alkyl;alternatively, R^(C) and R^(D) are taken together with the nitrogen atomto which they are bound to form a five to seven membered aromatic,partially aromatic or saturated ring structure; wherein the ringstructure optionally contains one to two additional heteroatoms selectedfrom O, N or S.

In an embodiment of the present invention Y is —CH₂—; Z is —CH₂—; R¹ isselected from the group consisting of hydrogen, C₁₋₄alkyl and—C₁₋₄alkyl-NR^(C)R^(D); R⁶ is hydrogen; a is 1; R² is selected from thegroup consisting of hydroxy and C₁₋₄alkoxy; b is an integer from 0 to 1;R³ is selected from the group consisting of oxo, C₁₋₄alkyl, amino,C₁₋₄alkylamino and di(C₁₋₄alkyl)amino;

is selected from the group consisting of cyclohexenyl, phenyl, thienyl,pyrrolyl, pyridyl, pyrazinyl and pyrazolyl; wherein R^(C) and R^(D) areindependently selected from hydrogen and C₁₋₄alkyl; alternatively, R^(C)and R^(D) are taken together with the nitrogen atom to which they arebound to form a five to seven membered aromatic, partially aromatic orsaturated ring structure; wherein the ring structure optionally containsone to two additional heteroatoms selected from O, N or S.

In another embodiment of the present invention, Y is —CH₂—; Z is —CH₂—;R¹ is selected from the group consisting of hydrogen, methyl and—C₁₋₄alkyl-NR^(C)R^(D); R⁶ is hydrogen; a is 1; R² is selected from thegroup consisting of hydroxy and methoxy; b is an integer from 0 to 1; R³is selected from the group consisting of oxo, methyl and amino;

is selected from the group consisting of cyclohexenyl, phenyl, thienyl,pyrrolyl, pyridyl, pyrazinyl and pyrazolyl.

Additional embodiments of the present invention, include those whereinthe substituents selected for one or more of the variables definedherein (i.e. X, Y, Z, a, b, R¹, R², R³, R⁶,

and

are independently selected to be any individual substituent or anysubset of substituents selected from the complete list as definedherein.

In an embodiment of the present invention, are compounds selected fromthose listed in any of the individual Tables below. In anotherembodiment of the present invention, are compounds selected from any ofthose listed in Table 3-6 below. In another embodiment of the presentinvention, are compounds selected from any of those listed in Table 2below.

In an embodiment of the present invention are compounds selected fromthe group listed in Table 1. In another embodiment of the presentinvention are compounds selected from the group listed in Table 3. Inanother embodiment of the present invention are compounds selected fromthe group listed in Table 4. In another embodiment of the presentinvention are compounds selected from the group listed in Table 5. Inanother embodiment of the present invention are compounds selected fromthe group listed in Table 6.

Representative compounds of the present invention are as listed in Table1 to 6 below. Unless otherwise noted, the compounds were prepared asmixtures of stereo-configuration (where applicable). In Tables 1, 2, 3and 4, wherein a structure is drawn for the

group, the symbol “

” is used to denote the position of bridging atoms. In Tables 4 and 6,the “

” symbol is used to denote the presence of an optional double bond (i.e.used to denote optional unsaturation of the designated bond).

TABLE 1 Compounds of Formula (I)

ID No R¹ R² R³ 1 hydrogen methoxy benzyloxy 2 4-(diethylamino-ethoxy)-methoxy benzyloxy benzyl- 3 4-(diethylamino-ethoxy)- methoxy hydroxybenzyl-

TABLE 2 Compounds of Formula (II)

    ID No.     Z     Y     R¹     (R²)_(a)

 4 —CH₂— —CH₂— methyl 4-hydroxy 2-thienyl  5 —CH2- —CH₂— methyl4-hydroxy 2-(N-methyl- pyrrolyl)  6 —CH₂— —CH₂— methyl 4-hydroxy2-pyridyl  65 —CH₂— —CH₂— methyl 3-methoxy

  (cyclohex-1- en-3-one)  75 —CH₂— —CH₂— methyl 4-hydroxy 2-thienyl  76—CH₂— —CH₂— methyl 4-hydroxy 2-(N-methyl- pyrrolyl)  80 —CH₂— —CH₂—methyl 4-hydroxy 2-pyridyl  91 —CH₂— —CH₂— methyl 4-methoxy

  (cyclohex-1- en-3-one)  93 —CH₂— —CH₂— methyl 4-hydroxy

  (cyclohex-1- en-3-one) 104 —CH₂— —CH₂— methyl 4-methoxy phenyl 105—CH₂— —CH₂— methyl 4-hydroxy phenyl 109 —CH₂— —CH₂— methyl 3-hydroxy2-pyridyl 110 —CH₂— —CH₂— methyl 4-hydroxy 4-pyridyl 111 —CH₂— —CH₂—methyl 4-hydroxy 2-pyrazinyl 112 —CH₂— —CH₂— dimethylamino- 4-hydroxy2-pyridyl ethyl- 113 —CH₂— —CH₂— H 4-methoxy 2-(2-methyl- pyrazolyl) 114—CH₂— —CH₂— methyl 4-methoxy 2-(2-methyl- pyrazolyl) 116 —CH₂— —CH₂— H4-methoxy 2-(3-amino- pyrazinyl)

TABLE 3 Compounds of Formula (II)

    ID No.     Z     Y     R¹     (R²)_(a)

 7 —CH₂— —S— H a = 0 phenyl  8 —CH₂— —S— ethyl 4-hydroxy phenyl  9 —CH₂——S— ethyl 4-methyl-carbonyl- phenyl oxy-  10 —CH₂— —S— ethyl4-methyl-sulfonyl- phenyl oxy-  11 —CH₂— —S— methyl 4-trifluoro-methyl-phenyl sulfonyl-oxy-  12 —CH₂— —S— methyl 4-chloro phenyl  13 —CH₂— —S—methylcarbonyl- 4-(t-butyl-dimethyl- phenyl silyloxy)-  14 —CH₂— —S—methylcarbonyl- 4-hydroxy phenyl  15 —CH₂— —S— H 4-chloro phenyl  16—CH₂— —S— H 4-fluoro phenyl  17 —CH₂— —S— methyl 4-(t-butyl-carbonyl-phenyl oxy)-  18 —CH₂— —S— methyl 4-(t-butyl-dimethyl- phenyl oxy)-  19—CH₂— —SO₂— methyl 4-(t-butyl-dimethyl- phenyl silyloxy)-  20 —CH₂— —S—methyl 4-(1,1,2,2,3,3,4,4,4- phenyl Nonafluorobutyl- sulfonyl-oxy)-  21—CH₂— —S— ethyl 4-methoxy phenyl  22 —CH₂— —SO₂— methyl 4-methoxy phenyl 23 —CH₂— —SO₂— methyl 4-hydroxy phenyl  24 —CH₂— —S— 4-(piperidinyl-4-hydroxy phenyl ethoxy)-benzyl-  25 —CH₂— —S— 4-(diethylamino-4-(t-butyl-dimethyl- phenyl ethoxy)-benzyl- silyloxy)-  26 —CH₂— —S—4-(piperidinyl- 4-(t-butyl-dimethyl- phenyl ethoxy)-benzyl- silyloxy)- 27 —CH₂— —S— H 4-methoxy phenyl  28 —CH₂— —O— H 4-methoxy phenyl  29—CH₂— —S— methyl 4-methoxy phenyl  30 —CH₂— —O— methyl 4-methoxy phenyl 32 —CH₂— —S— H 4-hdyroxy phenyl  33 —CH₂ —S— H 4-(t-butyl-dimethyl-phenyl silyloxy)-  34 —CH₂ —S— methyl 4-hydroxy phenyl  35 —CH₂ —O—methylcarbonyl- 4-methoxy phenyl  38 —CH₂— —O— H 4-methoxy3-(benzyloxy)- phenyl  39 —CH₂— —S— 4-(diethylamino- 4-methoxy phenylethoxy)-benzyl  40 —CH₂— —O— 4-(diethylamino- 4-methoxy phenylethoxy)-benzyl  41 —CH₂— —S— hydroxy 4-methoxy phenyl  42 —CH₂— —S—methyl 4-methyl phenyl  43 —CH₂— —S— methyl a = 0 phenyl  44 —CH₂— —S—methyl 4-fluoro phenyl  45 —CH₂— —S— H 4-methoxy 3-(methoxy)- phenyl  46—CH₂— —S— methyl 4-methoxy 3-(methoxy)- phenyl  47 —CH₂— —S— methyl4-methoxy 3-(hydroxy)- phenyl  48 —CH₂— —S— methyl 4-hydroxy3-(hydroxy)- phenyl  49 —CH₂— —S— H 4-hydroxy 3-(hydroxy)- phenyl  50—CH₂— —S— 4-(diethylamino- 4-hydroxy phenyl ethoxy)-benzyl  51 —CH₂——SO— methyl 4-(t-butyl-dimethyl- phenyl silyloxy)-  52 —CH₂— —SO— methyl4-hydroxy phenyl  53 —CH(OH)— —S— methyl 4-hydroxy phenyl  54 —CH₂— —SO—methyl 4-methoxy phenyl  55 —CH₂— —SO— H 4-methoxy phenyl  57 —CH₂— —S—methyl 4-bromo phenyl  59 —CH₂— —O— 4-(methyl- 4-methoxy phenylcarbonyloxy)- phenyl-carbonyl-  61 —CH₂— —S— 4-(piperidinyl- 4-methoxyphenyl ethoxy)-benzyl  63 —CH(OH)— —O— methyl 4-methoxy phenyl  66 —CH₂——O— H 4-fluoro phenyl  67 —CH₂— —O— H 4-bromo phenyl  68 —CH₂— —O—methyl 4-fluoro phenyl  69 —CH₂— —O— methyl 4-bromo phenyl  70 —C(CH₃)₂——O— methyl 4-hydroxy 3-(hydroxy)- phenyl  72 —CH₂— —S— methyl 4-hydroxy3-(carboxy)- phenyl  73 —CH₂— —O— methyl a = 0 phenyl  74 —CH₂— —O—methyl 4-carboxy phenyl  77 —CH₂— —S— methyl 4-cyano phenyl  78 —CH₂——S— methyl 4-hydroxy 4-(bromo)- phenyl  79 —CH₂— —S— methyl 4-hydroxy4-(fluoro)- phenyl  81 —CH₂— —S— methyl 4-methoxy 2-pyridyl  82 —CH₂——S— methyl 4-hydroxy 2-pyridyl  83 —CH₂— —S— methyl 2-hydroxy3-(fluoro)- phenyl  84 —CH₂— —S— methyl 4-hydroxy 3-(bromo)- phenyl  85—CH₂— —S— methyl 4-hydroxy 3-(fluoro)- phenyl  86 —CH₂— —S— methyl4-hydroxy 3-(trifluoro- methyl)-phenyl  87 —CH₂— —S— 3-(diethylamino-4-(t-butyl-carbonyl- phenyl ethoxy)-benzyl- oxy)-  88 —CH₂— —S—dimethylamino- 4-hydroxy phenyl ethyl-  89 —CH₂— —S— methyl 4-fluoro3-(fluoro)- phenyl  94 —CH₂— —S— methyl 4-methoxy-carbonyl phenyl  95—CH₂— —S— methyl 4-carboxy phenyl  96 —C(CH₃)₂— —S— H 4-methoxy3-(methoxy)- phenyl  97 —C(CH₃)₂— —S— methyl 4-methoxy 3-(methoxy)-phenyl  98 —CH₂— —S— H 4-(t-butyl-dimethyl- 3-(t-butyl- silyloxy)-dimethyl- silyloxy)-phenyl  99 —CH₂— —S— H 4-(t-butyl-carbonyl- phenyloxy)- 100 —CH₂— —S— methyl 3-hydroxy phenyl 101 —CH₂— —S— H 4-hydroxy2-pyridyl 102 —CH₂— —S— H 4-methoxy 2-pyridyl 103 —CH₂— —S— methyl4-methoxy 2-(2-methyl- pyridyl)  36 —S —CH₂— methyl 4-methoxy phenyl  37—S —CH₂— methyl 4-hydroxy phenyl  62 —S— —CH₂— 4-(piperidinyl- 4-methoxyphenyl ethoxy)-phenyl- carbonyl-

TABLE 4 Compounds of formula (II)

  ID NO     Z     Y     R⁶     (R²)_(a)

 71 —CH₂— —CH₂— methyl 3- hydroxy

  (cyclohex-1-en-3- one) 106 —CH₂— —CH═ methyl 4- methoxy

  (3-(3-methyl- piperidin-4-one)) 134 —CH₂— —CH═ methyl 4- hydroxy

  (3-(3-methyl- piperidin-4-one)) For compound #71,

 represents a single bond; for compounds #106 and #134,

 represents a double bond; as indicated by the designation of the Ysubstituent group in the table above.

TABLE 5 Compounds of Formula (II)

ID No R¹ Y (R²)_(a) (R³)_(b) 136 H —NH— 4-methoxy b = 0 137 H —N(CH₃)—4-methoxy 9-methoxy 138 methyl —N(CH₃)— 4-methoxy b = 0 139 methyl—N(CH₃)— 4-hydroxy 10-hydroxy 140 methyl —N(CH₃)— 4-hydroxy 10-methoxy141 methyl —N(CH₃)— 4-hydroxy b = 0

TABLE 6 Compounds of formula (II)

    ID No     Y    

    R¹     (R²)_(a)

126 —CH₂— single methyl 4-hydroxy phenyl 127 —CH₂— single H 4-methoxyphenyl 128 —CH₂— single methyl 4-methoxy phenyl 120 —S— double H4-methoxy phenyl 117 —S— single H 4-methoxy 3-(hydroxy)- phenyl 118 —S—single methyl 4-hydroxy phenyl 119 —S— single 4-(piperidinyl- 4-hydroxyphenyl ethoxy)-benzyl 121 —S— single 4-(piperidinyl- 4-methoxy phenylethoxy)-benzyl 123 —S— single methyl 4-methoxy phenyl 124 —S— singlemethyl 4-hydroxy phenyl 125 —S— single methyl 4-hydroxy 3-(methoxy)-phenyl 129 —S— single 4-(pyrrolidinyl- 4-methoxy phenyl ethoxy)-benzyl130 —SO— single H 4-methoxy phenyl

Additional representative intermediates or by-products in thepreparation of the compounds of formula (I) and/or compounds of formula(II) are as listed in Table 7.

TABLE 7 Representative Intermediates and/or By-Products

#31

#56

#58

#60

#122

#131

#133

#142

As used herein, the term “degenerative brain disease” shall includecognitive disorder, dementia, regardless of underlying cause,Alzheimer's disease, and the like.

As used herein, the term “cardiovascular disease” shall include elevatedblood lipid levels, coronary arthrosderosis, coronary heart disease, andthe like.

As used herein, the term “cerebrovascular disease” shall includeabnormal regional cerebral blood flow, ischemic brain damage, and thelike.

As used herein, the term “progestogen antagonist” shall includemifepristone (RU-486), J-867 (Jenapharm/TAP Pharmaceuticals), J-956(Jenapharm/TAP Pharmaceuticals), ORG-31710 (Organon), ORG-32638(Organon), ORG-31806 (Organon), onapristone (ZK98299) and PRA248(Wyeth). Further, as used herein, the terms “progestin” and“progesterone” are used interchangeably.

Estrogen receptor modulators are useful in the treatment and/orprevention of disorders and diseases mediated by one or more estrogenreceptor(s) including, but not limited to, as hot flashes, vaginaldryness, osteopenia, osteoporosis, hyperlipidemia, loss of cognitivefunction, degenerative brain diseases, cardiovascular diseases,cerebrovascular diseases, hormone sensitive cancers, hyperplasia (intissues including breast, endometrium, and cervix in women and prostatein men), endometriosis, uterine fibroids and osteoarthritis. Estrogenreceptor modulators are further useful as contraceptive agents eitheralone or in combination with a progestogen or progestogen antagonist.

Androgen receptor modulators are useful in the treatment and/orprevention of disorders and diseases mediated by one of more androgenreceptor(s) including, but not limited to, prostate carcinoma, benignprostatic hyperplasia (BPH), hirsitutism, alopecia, anorexia nervosa,breast cancer, acne, AIDS and cachexia. Androgen receptor modulators arefurther useful as a male contraceptive and/or as a male performanceenhancer

Progestin receptor modulators are useful in the treatment and/orprevention of disorders and diseases modulated by the progestinreceptor, including, but not limited to, endometriosis (preferablywithout associated with bone loss and/or hypoestrogenism), myoma(preferably without associated with bone loss and/or hypoestrogenism),dysfunctional bleeding. Progestin receptor modulators are further usefulas contraceptives either alone or in combination with one or moreestrogen receptor modulator(s). Progestin receptor modulators arefurther still useful as adjunct to estrogen in hormone replacementtherapy in postmenopausal women, as well as in the treatment of tumorscontaining steroid receptors.

As used herein, “halogen” shall mean chlorine, bromine, fluorine andiodine.

As used herein, the term “alkyl” whether used alone or as part of asubstituent group, include straight and branched chains. For example,alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, pentyl and the like. Similarly, the term“C₁₋₄alkyl” whether used alone or as part of a substituent group,include straight and branched chains containing 4 carbon atoms. Forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl and t-butyl.

As used herein, unless otherwise noted, the term “halogenated C₁₋₄alkyl”shall mean any C₁₋₄alkyl group as defined above substituted with atleast one halogen atom, preferably substituted with a least one fluoroatom. Suitable examples include but are not limited to —CF₃, —CH₂—CF₃,—CF₂—CF₂—CF₂—CF₃, and the like.

As used herein, unless otherwise noted, “alkoxy” whether used alone oras part of a substituent group, shall denote an oxygen ether radical ofthe above described straight or branched chain alkyl groups. Forexample, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxyand the like. Similarly, the term “C₁₋₄alkoxy” whether used alone or aspart of a substituent group, shall denote an oxygen ether radical of theabove described straight or branched chain C₁₋₄alkyl groups. Forexample, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, and the like.

As used herein, unless otherwise noted, “aryl” shall refer tounsubstituted carbocylic aromatic groups such as phenyl, naphthyl, andthe like.

As used herein, unless otherwise noted, “aralkyl” shall mean any loweralkyl group substituted with an aryl group such as phenyl, naphthyl andthe like. For example, benzyl, phenylethyl, phenylpropyl,naphthylmethyl, and the like.

As used herein, unless otherwise noted, the term “partially unsaturated”when referring to a ring structure shall mean any stable ring structurewhich contains at east one unsaturated bond. Suitable examples include,but are not limited to cyclohexenyl, and the like.

As used herein, unless otherwise noted, “heteroaryl” shall denote anyfive or six membered monocyclic aromatic ring structure containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to three additional heteroatoms independentlyselected from the group consisting of O, N and S; or a nine or tenmembered bicyclic aromatic ring structure containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heteroaryl group may beattached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to,pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl,isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl,isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl,benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, and the like. Preferred heteroaryl groupsinclude pyrrolyl, pyridyl, pyrazolyl, pyrazinyl, and the like.

As used herein, the term “heterocycloalkyl” shall denote any five toseven membered monocyclic, saturated or partially unsaturated ringstructure containing at least one heteroatom selected from the groupconsisting of O, N and S, optionally containing one to three additionalheteroatoms independently selected from the group consisting of O, N andS; or a nine to ten membered saturated, partially unsaturated orpartially aromatic bicyclic ring system containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heterocycloalkyl group maybe attached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to,pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl,pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl,dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl,chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl, and thelike. Preferred heterocycloalkyl groups include piperidinyl,morpholinyl, and the like.

As used herein, the notation “*” shall denote the presence of astereogenic center.

When a particular group is “substituted” (e.g., aryl, heterocycloalkyl,heteroaryl), that group may have one or more substituents, preferablyfrom one to five substituents, more preferably from one to threesubstituents, most preferably from one to two substituents,independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

As used herein, unless otherwise noted, the term “leaving group” shallmean a charged or uncharged atom or group which departs during asubstitution or displacement reaction. Suitable examples include, butare not limited to, Br, Cl, I, mesylate, tosylate, and the like.

As used herein, unless otherwise noted, the term “nitrogen protectinggroup” shall mean a group which may be attached to a nitrogen atom toprotect said nitrogen atom from participating in a reaction and whichmay be readily removed following the reaction. Suitable nitrogenprotecting groups include, but are not limited to carbamates—groups ofthe formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl,benzyl, phenylethyl, CH₂═CH—CH₂—, and the like; amides—groups of theformula —C(O)—R¹ wherein R¹ is for example methyl, phenyl,trifluoromethyl, and the like; N-sulfonyl derivatives—groups of theformula —SO₂—R″ wherein R″ is for example tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogenprotecting groups may be found in texts such as T. W. Greene & P. G. M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenyl-alkyl-amino-carbonyl-alkyl” substituentrefers to a group of the formula

Unless otherwise noted, when naming R² and R³ substituent groups on thecompounds of formula (I) and formula (II), the following numbering ofthe attachment atoms will be applied:

Unless otherwise noted, when naming the

ring, the first bridging carbon atom (counting clockwise as noted above)shall be denoted as in the 1-position with counting continued in aclockwise direction. Thus, for example, wherein the

ring is denoted as 4-thienyl, the compound of formula (I) will have thefollowing structure

One skilled in the art will recognize that wherein the compound offormula (II) Y is —CH═ or —N═ then the

symbol represent a double bond. Similarly, wherein the compound offormula (II) Y is other than —CH═ or —N═ then the

symbol represent a single bond.

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows:

-   -   18-Crown-6=1,4,7,10,13,16-hexaoxaxyxlooctadecane    -   BuLi or n-BuLi=n-Butyl lithium    -   DIPEA=Diethylisopropylamine    -   DMF=N,N-Dimethylformamide    -   DMSO=Dimethylsulfoxide    -   DTT=Dithiothreitol    -   EDTA=Ethylene diamine tetraacetic acid    -   ERT=Estrogen replacement therapy    -   Et=Ethyl (i.e —CH₂CH₃)    -   Etl=Ethyl Iodine    -   EtOAc=Ethyl acetate    -   EtOH=Ethanol    -   EtSH=Ethylthiol    -   HEPES=4-(2-Hydroxyethyl)-1-Piperizine Ethane Sulfonic Acid    -   HPLC=High Pressure Liquid Chromatography    -   HRT=Hormone replacement therapy    -   KO-t-Bu or t-Bu-OK=Potassium t-butoxide    -   Me=Methyl (i.e. —CH₃)    -   MeI=Methyl Iodide    -   MeOH=Methanol    -   NaBH₄=Sodium borohydride    -   NaOAc=Sodium Acetate    -   OXONE=Potassium monopersulfate triple salt    -   PBS=Phosphate buffered solution    -   Piv=Pivaloyl    -   PivCl=Pivaloyl Chloride    -   PPA=Polyphosphoric Acid    -   Py.HCl=Pyridine Hydrochloride    -   TBAF=Tetra(n-butyl)ammonium fluoride    -   TBS=Tert-butyl-dimethyl-silyl    -   TBSCl=Tert-butyl-dimethyl-silyl chloride    -   TEA or Et₃N=Triethylamine    -   Tf=Triflate (i.e. —O—SO₂—CF₃)    -   Tf₂O=Triflic anhydride    -   THF=Tetrahydrofuran    -   Tris HCl=Tris[hydroxymethyl]aminomethyl hydrochloride    -   TsOH=Tosic Acid

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

One skilled in the art will recognize that wherein a reaction step ofthe present invention may be carried out in a variety of solvents orsolvent systems, said reaction step may also be carried out in a mixtureof the suitable solvents or solvent systems.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts includethe following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

Representative acids and bases which may be used in the preparation ofpharmaceutically acceptable salts include the following:

acids including acetic acid, 2,2-dichloroactic acid, acylated aminoacids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid,benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid,(+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonicacid, capric acid, caproic acid, caprylic acid, cinnamic acid, citricacid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid,ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconicacid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolicacid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lacticacid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malicacid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinc acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitric acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid; and

bases including ammonia, L-arginine, benethamine, benzathine, calciumhydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

Compounds of formula (I) may be prepared according to the processoutlined in Scheme 1.

Accordingly, a suitably substituted compound of formula (III), a knowncompound or compound prepared by known methods is reacted with asuitably substituted compound of formula (IV), a known compound orcompound prepared by known methods, in an organic solvent such asethanol, methanol, isopropanol, t-butanol, and the like, at an elevatedtemperature in the range of from about 60° to about 150° C., preferablyat about reflux temperature, to yield the corresponding compound offormula (Ia).

The compound of formula (Ia) is further, optionally, reacted with asuitably substituted compound of formula (V), a known compound orcompound prepared by known methods, in the presence of a base such asNaH, NaHCO₃, Na₂CO₃, K₂CO₃, Na(C₁₋₄alkoxide) (such as sodium methoxide,sodium ethoxide, sodium t-butoxide, and the like), K(C₁₋₄alkoxide) (suchas potassium methoxide, potassium ethoxide, potassium t-butoxide, andthe like), TEA, DIPEA, pyridine, and the like, in an organic solventsuch as DMF, DMSO, THF, and the like, at a temperature in the range offrom about 0° C. to about reflux, preferably at a temperature in therange of from about 0° C. to about room temperature, to yield thecorresponding compound of formula (Ib).

One skilled in the art will recognize that wherein the compound offormula (I) X is —NR^(A)— and R^(A) is other then hydrogen (for example,wherein R^(A) is -L¹-R⁴-(L²)_(c)-R⁵), the compound of formula (I) may beprepared from the corresponding compound of formula (I) wherein X is—NH— according to the process outlined in Scheme 2.

Accordingly, a suitably substituted compound of formula (Ic), is reactedwith a suitably substituted compound of formula (VI), wherein J is aleaving group such as halogen, tosyl, mesyl, and the like, a knowncompound or compound prepared by known methods, in the presence of abase such as NaH, NaHCO₃, Na₂CO₃, K₂CO₃, Na(C₁₋₄alkoxide) (such assodium methoxide, sodium ethoxide, sodium t-butoxide, and the like),K(C₁₋₄alkoxide) (such as potassium methoxide, potassium ethoxide,potassium t-butoxide, and the like), TEA, DIPEA, pyridine, and the like,in an organic solvent such as DMF, DMSO, THF, and the like, at atemperature in the range of from about 0° C. to about reflux, preferablyat a temperature in the range of from about 0° C. to about roomtemperature, to yield the corresponding compound of formula (Id),wherein R^(A) is other than hydrogen.

One skilled in the art will further recognize that wherein the compoundof formula (I) one or more R² and/R³ groups are OH, said hydroxy groupsmay be further functionalized to prepare compounds of formula (I)wherein one or more R² and/or R³ groups are selected from —O-aralkyl,—C(O)—C₁₋₄alkyl, —C(O)O—C₁₋₄alkyl, —OC(O)—C₁₋₄alkyl, —O—SO₂—C₁₋₄alkyl or—O—SO₂— (halogenated C₁₋₄alkyl), according to known methods. Forexample, by reacting one or more of the OH substituent groups with asuitably substituted alkyl halide, acid chloride, sulfonyl chloride, andthe like.

Compounds of formula (II) may be similarly prepared according to theprocess outlined in Scheme 1 above, by selecting and substituting asuitably substituted compound of formula (VII)

a known compound or compound prepared by known methods, for the compoundof formula (II).

The present invention further comprises pharmaceutical compositionscontaining one or more compounds of formula (I) and/or compounds offormula (II) with a pharmaceutically acceptable carrier. Pharmaceuticalcompositions containing one or more of the compounds of the inventiondescribed herein as the active ingredient can be prepared by intimatelymixing the compound or compounds with a pharmaceutical carrier accordingto conventional pharmaceutical compounding techniques. The carrier maytake a wide variety of forms depending upon the desired route ofadministration (e.g., oral, parenteral). Thus for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives include water, glycols, oils, alcohols, flavoringagents, preservatives, stabilizers, coloring agents and the like; forsolid oral preparations, such as powders, capsules and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like. Solidoral preparations may also be coated with substances such as sugars orbe enteric-coated so as to modulate major site of absorption. Forparenteral administration, the carrier will usually consist of sterilewater and other ingredients may be added to increase solubility orpreservation. Injectable suspensions or solutions may also be preparedutilizing aqueous carriers along with appropriate additives.

To prepare the pharmaceutical compositions of this invention, one ormore of the compounds of the present invention selected as the activeingredient is intimately admixed with a pharmaceutical carrier accordingto conventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, through other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 50-100 mg and maybe given at a dosage of from about 0.5-5.0 mg/kg/day, preferably fromabout 1.0-3.0 mg/kg/day. The dosages, however, may be varied dependingupon the requirement of the patients, the severity of the conditionbeing treated and the compound being employed. The use of either dailyadministration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 500 mg ofthe active ingredient of the present invention. The tablets or pills ofthe novel composition can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterial can be used for such enteric layers or coatings, such materialsincluding a number of polymeric acids with such materials as shellac,cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating disorders mediated by one or more sex hormonereceptor described in the present invention may also be carried outusing a pharmaceutical composition comprising any of the compounds asdefined herein and a pharmaceutically acceptable carrier. Thepharmaceutical composition may contain between about 0.01 mg and 1000mg, preferably about 1 to 500 mg, more preferably, 10 to 100 mg of thecompound, and may be constituted into any form suitable for the mode ofadministration selected. Carriers include necessary and inertpharmaceutical excipients, including, but not limited to, binders,suspending agents, lubricants, flavorants, sweeteners, preservatives,dyes, and coatings. Compositions suitable for oral administrationinclude solid forms, such as pills, tablets, caplets, capsules (eachincluding immediate release, timed release and sustained releaseformulations), granules, and powders, and liquid forms, such assolutions, syrups, elixers, emulsions, and suspensions. Forms useful forparenteral administration include sterile solutions, emulsions andsuspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

The compound of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phophatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of disorders mediated by one or more sex hormonereceptor is required.

The daily dosage of the products may be varied over a wide range from0.01 to 1,000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250, 500 and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Aneffective amount of the drug is ordinarily supplied at a dosage level offrom about 0.01 mg/kg to about 300 mg/kg of body weight per day.Preferably, the range is from about 0.5 to about 5.0 mg/kg of bodyweight per day, most preferably, from about 1.0 to about 3.0 mg/kg ofbody weight per day. The compounds may be administered on a regimen of 1to 4 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

Example 1 7-methoxy-thiochroman-4-one

Following the procedure described in Speckamp, Willem N.; Westra, J. G.;Huisman, Henderikus O. Tetrahedron 1970, 26, 2353-63 the title compoundwas prepared as a colorless oil.

Example 2 7-Methoxy-1-methyl-2,3-dihydro-1H-quinolin-4-one

Following the procedure described in Speckamp, Willem N.; VanVelthuysen, J. A.; Pandit, U. K.; Huisman, H. O. Tetrahedron 1968, 24,5881-91 the title compound was prepared as a yellow oil.

Example 3 7-methoxy-2,2-dimethyl-thiochroman-4-one

Following the procedure described in Camps, F.; Colomina, O.; Coll, J.;Messeguer, A. Journal of Heterocyclic Chemistry 1983, 20, 1115-17 thetitle compound was prepared as a colorless oil.

Example 4 8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

7-methoxy-thiochroman-4-one (700 mg, 4.27 mmol) was stirred with(4-methoxy-phenyl)-hydrazine (818 mg, 4.70 mmol, 1.1 eq.) in EtOH (40mL, 0.1 M) and refluxed for 2 hours. EtOH was then removed from themixture and EtOAc and saturated NaHCO₃ aqueous solution were added. Theorganic layer was separated, dried over K₂CO₃ and concentrated. Theresidue was purified with flash column chromatography (4:1 Hexane:EtOAc)to yield the title product as a brown solid.

MS (m/z): MH⁻ (266)

¹H NMR (CDCl₃) δ 8.18 (broad s, 1H), 7.32-6.85 (m, 7H), 4.14 (s, 2H),3.89 (s, 3H)

Example 5 6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 4, usingIsothiochroman-4-one (1.64 g, 10.0 mmol) as the starting material, thetitle compound was prepared as a brown solid.

¹H NMR (CDCl3) δ 8.25 (br. 1H), 7.55-7.10 (m, 8H), 4.20 (s, 2H)

Ms (m/z): MH⁺ (236)

Example 6 8-n ethoxy-5,11-dihydro-6-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 4, isothiochroman-4-one(460 mg, 2.805 mmol) was used as the starting material to yield thetitle compound as a brown solid.

MS (m/z): MH⁺ (268), MH⁻ (266)

¹H NMR (CDCl₃) δ 8.26 (broad s, 1H), 7.34-6.86 (m, 7H), 3.99 (s, 2H),3.83 (s, 3H)

Example 7 8-methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene

Following the procedure described in Example 4, using chroman-4-one (540mg, 3.65 mmol) as the starting material, the title compound was preparedas a brown solid.

MS (m/z): MH⁺ (252), MH⁻ (250)

¹H NMR (CDCl₃) δ 8.11 (broad s, 1H), 7.21-6.81 (m, 7H), 5.58 (s, 2H),3.83 (s, 3H)

Example 8 9-methoxy-6,7-dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulene

Following the procedure described in Example 4, using3,4-dihydro-2H-benzo[b]thiepin-5-one (0.5 g, 2.8 mmol) as the startingmaterial, the title compound was prepared as a brown solid.

MS (m/z): MH⁺ (282)

¹H NMR (CDCl₃) δ 7.94-6.86 (m, 7H), 3.88 (s, 3H), 3.39 (m, 2H, J=6.6Hz), 3.21 (m, 2H, J=6.6 Hz)

Example 9 8-fluoro-6,11,dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 4, using(4-fluoro-phenyl)-hydrazine (918 mg, 5.65 mmol) as the startingmaterial, the title compound was prepared as a brown solid.

¹H NMR (CDCl₃) δ 8.15 (s, 1H), 7.28-6.82 (m, 7H), 4.18 (s, 2H)

Example 108-methoxy-6,6-dimethyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 4, using7-methoxy-2,2-dimethyl-thiochroman-4-one (3.0 g, 13.5 mmol) as thestarting material, the title compound was prepared as a brown solid.

MS (m/z): MH⁺ (326), MH⁻ (324)

¹H NMR (CDCl₃) δ 8.02 (s, 1H), 7.29-6.63 (m, 6H), 3.88 (s, 3H), 3.78 (s,3H), 1.82 (s, 6H)

Example 11 8-chloro-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 4, using(4-chloro-phenyl)-hydrazine (872 mg, 4.871 mmol) as the startingmaterial, the title compound was prepared as a brown solid.

MS (m/z): MH⁻ (270)

¹H NMR (CDCl₃) δ 8.25 (s, 1H), 7.42-7.08 (m, 7H), 4.16 (s, 2H)

Example 12 8-bromo-6,11-dihydro-5-thia-aza-benzo[a]fluorene

Following the procedure described in Example 4, using(4-bromo-phenyl)-hydrazine (3.2 g, 20.0 mmol) as the starting material,the title compound was prepared as a white solid.

1H NMR (CDCl3) δ 8.55 (br. 1H), 7.60-7.15 (m, 7H), 4.18 (s, 2H)

Ms (m/z): MH+ (316)

Example 13 3,8-dimethoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the same procedure in Example 4, using7-methoxy-thiochroman-4-one (1.25 g, 6.44 mmol) as the startingmaterial, the title compound was prepared as a brown solid.

MS (m/z): MH⁺ (298), MH⁻ (296)

¹H NMR (CDCl₃) δ 8.05 (broad s, 1H), 7.26-6.69 (m, 6H), 4.18 (s, 2H),3.81 (s, 3H), 3.76 (s, 3H)

Example 14 2-bromo-8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 4, using6-bromo-thiochroman-4-one (0.6 g, 2.5 mmol) as the starting material,the title compound was prepared as a white solid.

¹H NMR (CDCl3) δ 8.35 (br. 1H), 7.45-6.85 (m, 6H), 3.85 (s, 3H), 3.80(s, 2H)

Ms (m/z): MH+ (346)

Example 152-fluoro-8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 4, using6-fluoro-thiochroman-4-one (1.47 g, 0.8 mmol) as the starting material,the title compound was prepared as a white solid.

1H NMR (CDCl3) δ 8.28 (br. 1H), 7.35-6.85 (m, 6H), 4.15 (s, 2H), 3.85(s, 3H)

Ms (m/z): MH+ (284)

Example 16 3-bromo-8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 4, using6-bromo-isothiochroman-4-one (1.2 g, 5.0 mmol) as the starting materialto yield the title compound as a brown solid.

1H NMR (CDCl3) δ 8.05 (br. 1H), 7.45-6.90 (m, 6H), 4.20 (s, 2H), 3.85(s, 3H)

Ms (m/z): MH+ (345)

Example 178-methoxy-3-trifluoromethyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 4, using6-trifluoromethyl-isothiochroman-4-one (1.15 g, 5.0 mmol), as thestarting material to yield the title compound as a brown solid.

1H NMR (CDCl3) δ 8.25 (br. 1H), 7.55-6.90 (m, 6H), 4.15 (s, 2H), 3.85(s, 3H)

Ms (m/z): MH+ (335)

Example 183-fluoro-8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 4, using6-fluoro-isothiochroman-4-one (900 mg, 5.0 mmol) as the startingmaterial, the title compound was prepared as a brown solid.

1H NMR (CDCl3) δ 8.05 (br. 1H), 7.40-6.85 (m, 6H), 4.15 (s, 2H), 3.85(s, 3H)

Ms (m/z): MH+ (284)

Example 19 8-fluoro-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene

Following the procedure described in Example 4, using4-fluoro-phenylhydrazine HCl salt (1.23 g, 7.57 mmoL) as the startingmaterial, the title compound was prepared as a brown solid.

¹H NMR (CDCl₃) δ 8.20 (br, s, 1H), 7.65˜6.80 (m, 7H), 5.38 (s, 2H).

MS (m/z): MH+, 240.

Example 20 8-bromo-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene

Following the procedure described in Example 4, using chroman-4-one(3.21 g, 21.7 mmoL) and 4-bromo-phenylhydrazine HCl salt (5.33 g, 23.8mmoL) as the starting material, the title compound was prepared as abrown solid.

¹H NMR (CDCl₃) δ 8.18 (br, s, 1H), 7.70˜6.75 (m, 7H), 5.40 (s, 2H).

MS (m/z): MH+, 300.

Example 21 3,8-difluoro-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 4, using6-fluoro-isothiochroman-4-one (900 mg, 5.0 mmol) as the startingmaterial, the title compound was prepared as a brown solid.

1H NMR (CDCl3) δ 8.00 (br. 1H), 7.55-6.95 (m, 6H), 4.00 (s, 2H)

Ms (m/z): MH+ (273)

Example 22 8-benzyloxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene

Following the procedure described in Example 4, using(4-benzyloxy-phenyl)-hydrazine hydrochloride salt and Chroman-4-one(2.93 g, 16.84 mmol) as the starting material, the title compound wasprepared as a brown solid.

MS (m/z): MH⁺ (358)

¹H NMR (CDCl₃) δ 8.05 (broad s, 1H), 7.42-6.58 (m, 11H), 5.54 (s, 2H),5.05 (s, 2H), 3.86 (s, 3H).

Example 23 8-Methoxy-5,11-dihydro-6H-benzo[a]carbazole

Following the procedure described in Example 4, using3,4-dihydro-2H-naphthalen-1-one (2.90 g, 20 mmoL) and4-methoxy-phenylhydrazine HCl salt as the starting material, the titlecompound was prepared as a brown solid.

¹H NMR (CDCl₃) δ 8.30 (br, s, 1H), 8.05˜6.80 (m, 7H), 3.90 (s, 3H), 3.08(t, J=10.5 Hz, 2H), 2.75 (t, J=10.5 Hz, 2H).

MS (m/z): MH+, 250.

Example 249-methoxy-5,6,7,12-tetrahydro-benzo[6,7]cyclohepta[1,2-b]indole

Following the procedure described in Example 4, using6,7,8,9-tetrahydro-benzocyclohepten-5-one (1.10 g, 6.87 mmoL) and4-methoxy-phenylhydrazine HCl salt (1.20 g, 6.87 mmoL) as the startingmaterial, the title compound was prepared as a brown solid.

¹H NMR (CDCl₃) δ 8.20 (br, s, 1H) 7.40˜6.80 (m, 7H) 3.95 (s, 3H), 2.75(m, J=9.5 Hz, 4H), 2.35 (m, J=9.5 Hz, 2H).

MS (m/z): MH+, 264.

Example 25 8-fluoro-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene

Following the procedure described in Example 4, using(4-fluoro-phenyl)-hydrazine hydrochloride salt and chroman-4-one (2.5 g,17 mmol) as the starting material, the title compound was prepared as abrown solid.

MS (m/z): MH⁺ (240)

Example 26 8-bromo-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene

Following the procedure described in Example 4, using(4-bromo-phenyl)-hydrazine hydrochloride salt and chroman-4-one (3.0 g,20 mmol) as the starting material, the title compound was prepared as abrown solid.

MS (m/z): MH⁺ (301)

Example 27 3-Methoxy-10H-benzo[4,5]furo[3,2-b]indole

Following the procedure described in Example 4, using benzofuran-3-one(3.0 g, 30 mmol) as the starting material, the title compound wasprepared as a brown solid.

MS (m/z): MH⁺ (238)

Example 28 7-Benzyloxy-3-methoxy-10H-benzo[4.5]furo[3,2-b]indole

Following the procedure described in Example 4, using6-benzyloxy-benzofuran-3-one (2.7 g, 11.2 mmol) as the startingmaterial, the title compound was prepared as a brown solid.

MS (m/z): MH⁺ (344)

Example 29 8-methoxy-5,11-dihydro-6H-indolo[3,2-c]quinoline

Following the procedure described in Example 4, using2,3-dihydro-1H-quinolin-4-one (500 mg, 3.4 mmol) as the startingmaterial, the title compound was prepared as a brown solid.

¹H NMR (CDCl₃) δ 7.85-6.60 (m, 7H), 4.50 (br. 1H), 3.70 (s, 2H), 3.20(s, 3H)

MS (m/z): MH⁺ (251)

Example 303-Fluoro-10-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorine

Following the procedure described in Example 4, starting with6-fluoro-isothiochroman-4-one (900 mg, 5.0 mmol), the title compound wasprepared as a brown solid.

1H NMR (CDCl3) δ 8.75 (br. 1H), 7.45-6.85 (m, 6H), 4.15 (s, 2H), 3.85(s, 3H)

Ms (m/z): MH+ (284)

Example 31 9-methoxy-6,11,dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 4, starting withisothiochroman-4-one (1.64 g, 10.0 mmol), the title compound was prepareas a brown solid.

1H NMR (CDCl3) δ 8.35 (br. 1H), 7.45-6.85 (m, 7H), 3.85 (s, 3H), 3.80(s, 2H)

Ms (m/z): MH+ (267)

Example 32 2,8-Dimethoxy-5-methyl-5,11-dihydro-6H-indolo[3,2-c]quinoline

Following the procedure described in Example 19, using7-methoxy-1-methyl-2,3-dihydro-1H-quinolin-4-one (3.5 g, 18.3 mmol) asthe starting material, the title compound was prepared as a white solid.

MS (m/z): MH⁺ (295)

Example 333,8-dimethoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

CH₃I (108 mg, 0.758 mmol, 1.5 eq.) was added to a mixture of3,8-dimethoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (150 mg, 0.505mmol) and NaH (61 mg, 60% in mineral oil, 1.515 mmol, 3.0 eq.) in DMF.The reaction mixture was then stirred at 25° C. for 2 hours. Thereaction mixture was partitioned between EtOAc and saturated NaHCO₃aqueous solution. The aqueous layer was extracted three times withEtOAc. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated to yield a crude material.The crude material was purified by silica gel (Hexanes to EtOAc 4:1) toyield the title compound as a brown solid.

MS (m/z): MH⁺ (312)

¹H NMR (CDCl₃) δ 7.51˜6.78 (m, 6H), 4.05 (s, 2H), 3.87 (s, 3H), 3.85 (s,3H), 3.78 (s, 3H)

Example 343,8-dimethoxy-6,6,11-trimethyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 33, starting with8-methoxy-6,6-dimethyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (1.25g, 3.84 mmoL), the title compound was prepared as a brown solid.

¹H NMR (CDCl₃) δ 8.01˜6.65 (m, 6H), 3.90 (s, 3H), 3.85 (s, 3H), 3.62 (s,3H), 1.80 (s, 6H).

MS (m/z): MH+, 340

Example 358-methoxy-11-methyl-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene

Following the procedure described in Example 33, using8-methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (250 mg, 0.996mmol) as the starting material, the title compound was prepared as awhite solid.

MS (m/z): MH⁺ (266)

¹H NMR (CDCl₃) δ 7.58-6.88 (m, 7H), 5.44 (s, 2H), 3.93 (s, 3H), 3.83 (s,3H)

Example 36 11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 33, using6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (236 mg) as the startingmaterial, the title compound was prepared as a white solid.

¹H NMR (CDCl₃) δ 7.50-7.15 (m, 8H), 4.08 (s, 2H), 3.92 (t, 3H)

MS (m/z): MH⁺ (250)

Example 37 8,11-diethyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 33, using6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (250 mg) as a startingmaterial, the title compound was prepared as a white solid.

¹H NMR (CDCl₃) δ 7.62-7.10 (m, 7H), 4.08 (s, 2H), 3.92 (t, 3H), 2.46 (s,3H)

MS (m/z): MH⁺ (266)

Example 388-Chloro-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 33, using8-chloro-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (540 mg, 1.99 mmol)as the starting material, the title compound was prepared as a whitesolid.

¹H NMR (CDCl₃) δ 7.56-7.08 (m, 7H), 4.05 (s, 2H), 3.84 (s, 3H)

Example 39 8-bromo-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure as described in Example 33, using8-bromo-6,11-dihydro-5-thia-aza-benzo[a]fluorene (600 mg) as thestarting material, the title compound was prepared as a white solid.

¹H NMR (CDCl₃) δ 7.65-7.15 (m, 7H), 4.00 (s, 2H), 3.92 (t, 3H)

MS (m/z): MH+ (330)

Example 40 8-fluoro-11-methyl-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene

Following the procedure as described in Example 33, using8-fluoro-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (1.02 g, 4.27 mmoL)as the starting material, the title compound was prepared as a whitesolid.

¹H NMR (CDCl₃) δ 7.62˜6.95 (m, 7H), 5.40 (s, 2H), 3.95 (s, 3H).

MS (m/z): MH+, 254.

Example 41 8-bromo-11-methyl-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene

Following the procedure as described in Example 33, using8-bromo-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (1.05 g, 3.50 mmoL)as the starting material, the title compound was prepared as a whitesolid.

¹H NMR (CDCl₃) δ 7.62˜6.95 (m, &H), 5.38 (s, 2H), 3.95 (s, 3H).

MS (m/z): MH+, 314.

Example 423-Bromo-8-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 33, using3-bromo-8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (680 mg,2.0 mmol) as the starting material, the title compound was prepared as awhite solid.

¹H NMR (CDCl₃) δ 7.55-6.65 (m, 6H), 4.10 (s, 3H), 4.00 (s, 2H), 3.90 (s,3H)

MS (m/z): MH+ (359)

Example 43 8-methoxy-11-methyl-5,11-dihysro-6H-benzo[a]carbazole

Following the procedure as described in Example 33, using8-methoxy-5,11-dihydro-6H-benzo[a]carbazole (0.85 g, 3.41 mmoL) as thestarting material, the title compound was prepared as a white solid.

¹H NMR (CDCl₃) δ 7.64˜6.82 (m, 7H), 4.05 (s, 3H), 3.92 (s, 3H), 3.05 (t,J=11.5 Hz, 2H), 2.90 (t, J=11.5 Hz, 2H).

MS (m/z): MH+, 264.

Example 449-methoxy-12-methyl-5,6,7,12-tetrahydro-benzo[6,7]cyclohepta[1,2-b]indole

Following the procedure as described in Example 33, using9-methoxy-5,6,7,12-tetrahydro-benzo[6,7]cyclohepta[1,2-b]indole (1.05 g,3.99 mmoL) as the starting material, the title compound was prepared asa white solid.

¹H NMR (CDCl₃) δ 7.35˜6.85 (m, 7H), 3.92 (s, 3H), 3.84 (s, 3H0, 2.68 (m,J=8.5 Hz, 4H), 2.28 (m, J=8.5 Hz, 2H).

MS (m/z): MH+, 278.

Example 458-methoxy-11-methyl-3-trifluoromethyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorine

Following the procedure described in Example 33, using with8-methoxy-3-trifluoromethyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene(670 mg, 2.0 mmol) as the starting material, the title compound wasprepared as a white solid.

¹H NMR (CDCl₃) δ 7.75-6.95 (m, 6H), 4.10 (s, 2H), 3.85 (s, 3H), 3.80 (s,3H)

MS (m/z): MH+ (349).

Example 469-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 33, using9-methoxy-6,11,dihydro-5-thia-11-aza-benzo[a]fluorene (530 mg, 2.0 mmol)as the starting material, the title compound was prepared as a whitesolid.

¹H NMR (CDCl₃) δ 7.65-6.80 (m, 7H), 4.08 (s, 2H), 3.85 (s, 6H)

MS (m/z): MH+ (280)

Example 473-Fluoro-10-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorine

Following the procedure described in Example 33, using3-Fluoro-10-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorine (285 mg,1.0 mmol) as the starting material, the title compound was prepared as awhite solid.

¹H NMR (CDCl₃) δ 7.55-6.65 (m, 6H), 4.10 (s, 3H), 4.00 (s, 2H), 3.90 (s,3H)

MS (m/z): MH+ (299)

Example 483-fluoro-8-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorine

Following the procedure described in Example 33, using3-fluoro-8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (285 mg,1.0 mmol) as the starting material, the title compound was prepared as awhite solid.

¹H NMR (CDCl₃) δ 7.55-6.65 (m, 6H), 4.10 (s, 3H), 4.00 (s, 2H), 3.90 (s,3H)

MS (m/z): MH+ (299)

Example 493,8-difluoro-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 33, using3,8-difluoro-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (273 mg) as thestarting material, the title compound was prepared as a white solid.

¹H NMR (CDCl₃) δ 7.60-6.55 (m, 6H), 4.00 (s, 2H), 3.90 (s, 3H)

MS (m/z): MH+ (288)

Example 508-fluoro-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 33, using8-fluoro-6,11-dihydro-5-thia-11-aza-benzo[a]fluorine (525 mg, 2.06 mmol)as the starting material, the title compound was prepared as a whitesolid.

MS (m/z): MH⁻ (268)

¹H NMR (CDCl₃) δ 7.58-6.83 (m, 7H), 3.98 (s, 2H), 3.87 (s, 3H)

Example 51 8-fluoro-11-methyl-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene

Following the procedure described in Example 33, using8-fluoro-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (1.02 g, 4.26 mmol)as the starting material, the title compound was prepared as a whitesolid.

¹H NMR (CDCl₃) δ 7.58-6.83 (m, 7H), 5.41 (s, 2H), 3.96 (s, 3H)

Example 528-methoxy-11-methyl-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene

Following the procedure described in Example 33, using8-methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (9.3 g, 63 mmoL) asthe starting material, the title compound was prepared as a white solid.

¹H NMR (CDCl₃) δ 7.65˜6.85 (m, 7H), 5.45 (s, 2H), 3.95 (s, 3H), 3.85 (s,3H).

MS (m/z): MH+, 266.

Example 53 8-bromo-11-methyl-6,110dihydro-5-oxa-11-aza-benzo[a]fluorene

Following the procedure described in Example 33, using8-bromo-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorine (1.05 g, 3.50 mmol)as the starting material, the title compound was prepared as a whitesolid.

¹H NMR (CDCl₃) δ 7.58-6.93 (m, 7H), 5.38 (s, 2H), 3.94 (s, 3H)

Example 548-Methoxy-11-methyl-5,11-dihydro-6-thia-11-aza-benzo[a]fluorene

Following the procedure as described in Example 33, using8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorine (240 mg, 0.899mmol) as the starting material, the title compound was prepared as awhite solid.

MS (m/z): MH⁺ (282)

¹H NMR (CDCl₃) δ7.53-6.88 (m, 7H), 3.96 (s, 3H), 3.88 (s, 2H), 3.85 (s,3H)

Example 5511-ethyl-8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure as in Example 33, using8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (1.00 g, 3.75mmol) and Etl (878 mg, 5.63 mmoL) as the starting material, the titlecompound was prepared as a white solid.

MS (m/z): MH⁻ (294)

¹H NMR (CDCl₃) δ 7.42-6.78 (m, 7H), 4.18 (q, 2H, J=6.4 Hz), 3.92 (s,2H), 3.78 (s, 3H), 1.34 (t, 3H, J=6.4 Hz)

Example 56 8-methoxy-5,11-dimethyl-5,11-dihydr-6H-indolo[3,2-c]quinoline

Following the procedure described in Example 33, using8-methoxy-5,11-dihydro-6H-indolo[3,2-c]quinoline (500 mg, 2 mmol) as thestarting material, the title compound was prepared as a white solid.

¹H NMR (CDCl₃) δ 8.0-6.70 (m, 7H), 3.75 (s, 3H), 3.13 (s, 2H), 3.00 (s,3H)

Example 572,8-Dimethoxy-5,11-dimethyl-5,11-dihydro-6H-indolo[3,2-c]quinoline

Following the procedure described in Example 33, using2,8-Dimethoxy-5-methyl-5,11-dihydro-6H-indolo[3,2-c]quinoline (1.3 g,4.42 mmol) as the starting material, the title compound was prepared asa white solid.

MS (m/z): MH⁺ (309)

Example 58 6,11-dihydro-5-thia-11-aza-benzo[a]fluorene-3,8-diol

A mixture of 3,8-dimethoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene(805 mg, 2.69 mmol) and Py.HCl (3.11 g, 26.9 mmol, 10 eq.) was heated to210° C. for 30 minutes. The reaction mixture was then partitionedbetween EtOAc and saturated NaHCO₃ aqueous solution. The aqueous layerwas extracted three times with EtOAc. The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to yield a crude material. The crude material was purifiedby silica gel (EtOAc to CH₂Cl₂:MeOH 5:1) to yield the title compound asa brown solid.

MS (m/z): MH⁺ (270)

Example 5912-methyl-6,7-dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulen-9-ol

Following the procedure described in Example 58, using9-methoxy-12-methyl-6,7-dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulene(495 mg, 1.0 mmol) as the starting material, the title compound wasprepared as a white solid.

MS (m/z): MH⁺ (282), MH⁻ (280)

¹H NMR (CDCl₃) δ 7.89 (br s, 1H), 7.68-6.75 (m, 7H), 3.38 (t, 2H, J=6.6Hz), 3.18 (t, 2H, J=6.6 Hz), 1.61 (br s, 3H)

Example 6011-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene-3,8-diol and8-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-3-ol

Following the procedure in Example 58, starting from3,8-dimethoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (95mg, 0.304 mmol),11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene-3,8-diol wasprepared as a brown solid and8-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-3-ol wasprepared as a white solid respectively.

8-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-3-ol

MS (m/z): MH⁺ (298), MH⁻ (296)

¹H NMR (CDCl₃) δ 7.52˜6.78 (m, 6H), 4.04 (s, 2H), 3.92 (s, 3H), 3.84 (s,3H).

11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene-3,8-diol

MS (m/z): MH⁺ (284)

Example 61 5,11-dimethyl-5,11-dihydro-6H-indolo[3,2-c]quinoline-2,8-dioland 2-methoxy-5,11-dimethyl-5,11-dihydro-6H-indolo[3,2-c]quinolin-8-ol

Following the procedure in Example 58, using2,8-dimethoxy-5,11-dimethyl-5,11-dihydro-6H-indolol[3,2-c]quinoline (150mg) as the starting material,5,11-dimethyl-5,11-dihydro-6H-indolo[3,2-c]quinoline-2,8-diol as wasobtained a brown solid and2-methoxy-5,11-dimethyl-5,11-dihydro-6H-indolo[3,2-c]quinolin-8-ol wasobtained as a white solid.

5,11-dimethyl-5,11-dihydro-6H-indolo[3,2-c]quinoline-2,8-diol

MS (m/z): MH⁺ (299)

¹H NMR (CDCl₃) δ 7.19-6.72 (m, 6H), 3.58 (s, 3H), 3.36 (t, 2H, J=6.4Hz), 2.89 (br s, 2H)

2-methoxy-5,11-dimethyl-5,1,1-dihydro-6H-indolo[3,2-c]quinolin-8-ol

MS (m/z): MH⁺ (312)

¹H NMR (CDCl₃) δ 7.29-6.79 (m, 6H), 3.89 (s, 3H), 3.73 (s, 3H), 3.49 (t,2H, J=6.8 Hz), 2.95 (br s, 2H)

Example 62 11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol

Following the procedure in Example 58, using8-Methoxy-11-methyl-5,11-dihydro-6-thia-11-aza-benzo[a]fluorene (61 mg,0.217 mmol) as the starting material, the title compound was prepared asa white solid.

MS (m/z): MH⁺ (268)

¹H NMR (CDCl₃) δ 7.48-6.85 (m, 7H), 4.71 (s, 1H), 3.93 (s, 3H), 3.83 (s,2H)

Example 63 11-methyl-6,11-dihydro-5-thia-aza-benzo[a]fluoren-8-ol

Following the procedure in Example 58, using8-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (75 mg,0.268 mmol) as the starting material, the title compound was prepared asa white solid.

¹H NMR (CDCl₃) δ 7.32-6.85 (m, 7H), 4.02 (s, 2H), 3.93 (s, 3H).

Example 642-bromo-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol

Following the procedure described in Example 33, using2-bromo-8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (340 mg,1.0 mmol),2-bromo-8-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorinewas prepared as a crude product. The crude product was further reactedaccording to the procedure as described in Example 58, to yield thetitle compound as a brown solid.

¹H NMR (CDCl₃) δ 7.72-6.85 (m, 6H), 4.00 (s, 2H), 3.90 (s, 3H)

MS (m/z): MH+ (344)

Example 652-fluoro-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol

Following the procedure described in Example 33, starting from2-fluoro-8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (700 mg,2.30 mmol),2-fluoro-8-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorinewas prepared as a crude product. The crude product was then furtherreacted according to the procedure described in Example 58, to yield thetitle compound as a brown solid.

¹H NMR (CDCl₃) δ 7.45-6.80 (m, 6H), 3.95 (s, 2H), 3.85 (s, 3H)

MS (m/z): MH+ (284)

Example 66 11-methyl-5,11-dihydro-6H-benzo[a]carbazol-8-ol

Following the procedure in Example 58, using8-methoxy-11-methyl-5,11-dihydro-6H-benzo[a]carbazole (780 mg, 2.96mmoL) as the starting material, the title compound was prepared as awhite solid.

¹H NMR (CDCl₃) δ 7.62˜6.78 (m, 7H), 4.80 (s, 3H), 3.95 (s, 3H), 2.95 (t,J=10.5 Hz, 2H), 2.80 (t, J=10.5 Hz, 2H).

MS (m/z): MH+, 250, MH−, 248.

Example 6712-Methyl-5,6,7,12-tetrahydro-benzo[6,7]cyclohepta[1,2-b]indol-9-ol

Following the procedure in Example 58, using9-methoxy-12-methyl-5,6,7,12-tetrahydro-benzo[6,7]cyclohepta[1,2-b]indole(896 mg, 3.23 mmoL) as the starting material, the title compound wasprepared as a white solid.

¹H NMR (CDCl₃) δ 7.42˜6.78 (m, 8H), 3.75 (s, 3H), 2.65 (t, J=10.5 Hz,2H), 2.20 (m, J=10.5 Hz, 2H).

MS (m/z): MH+, 264.

Example 686,6,11-trimethyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene-3,8-diol

Following the procedure in Example 58, using3,8-dimethoxy-6,6,11-trimethyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene(720 mg, 2.12 mmoL) as the starting material, the title compound wasprepared as a white solid.

¹H NMR (CDCl₃) δ 7.48˜6.68 (m, 8H), 3.60 (s, 3H), 1.78 (s, 6H).

MS (m/z): MH+, 312, MH−, 310.

Example 6911-methyl-3-trifluoromethyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol

Following the procedure described in Example 58, using8-methoxy-11-methyl-3-trifluoromethyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene(349 mg) as the starting material, the title compound was prepared as awhite solid.

¹H NMR (CDCl₃) δ 7.75-6.85 (m, 6H), 5.80 (br, 1H), 4.00 (s, 2H), 3.85(s, 3H)

MS (m/z): MH+ (334)

Example 703-fluoro-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol

Following the procedure described in Example 58, using3-fluoro-8-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorineas the starting material, the title compound was prepared as a brownsolid.

¹H NMR (CDCl₃) δ 7.55-6.82 (m, 6H), 5.20 (br, 1H), 3.95 (s, 2H), 3.82(s, 3H)

MS (m/z): MH+ (285)

Example 71 11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-9-ol

Following the procedure described in Example 58, using9-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (280 mg,1 mmol) as the starting material, the title compound was prepared as abrown solid.

¹H NMR (CDCl₃) δ 7.62-6.70 (m, 7H), 4.08 (s, 2H), 3.85 (s, 3H)

MS (m/z): MH+ (266)

Example 723-fluoro-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-10-ol

Following the procedure described in Example 58, using3-Fluoro-10-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorine(290 mg) as the starting material, the title compound was prepared as abrown solid.

¹H NMR (CDCl₃) δ 7.55-6.55 (m, 6H), 6.20 (br, 1H), 4.00 (s, 2H), 3.90(s, 3H)

MS (m/z): MH+ (286).

Example 733-bromo-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol

Following the procedure described in Example 58, using3-Bromo-8-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorine(359 mg), the title compound was prepared as a brown solid.

¹H NMR (CDCl₃) δ 7.52-6.85 (m, 6H), 4.10 (s, 2H), 3.85 (s, 3H)

MS (m/z): MH+ (346)

Example 743-ethylsulfanylmethyl-2-(2-hydroxy-phenyl)-1-methyl-1H-indol-5-ol

A mixture of9-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorine (95 mg,0.358 mmol), EtSH (1.434 mmol. 4.0 eq.), and AlCl₃ (1.792 mmol, 5.0 eq.)in CH₂Cl₂ was stirred at 25° C. for 5 hours. The reaction mixture wasthen cooled to 0° C. and quenched with saturated aqueous NaHCO₃solution. The aqueous solution was extracted with CH₂Cl₂ and the organiclayers were dried and concentrated to yield a crude product. The crudeproduct was purified by flash chromatograph to yield the title compoundas a brown solid.

MS (m/z): MNa⁺ (336), MH⁻ (312)

¹H NMR (CDCl₃) δ 7.32-6.78 (m, 7H), 3.75 (d, 1H, J=13.1 Hz), 3.65 (d,1H, J=13.1 Hz), 3.40 (s, 3H), 2.38 (q, 2H, J=6.5 Hz), 1.04 (t, 3H, J=6.5Hz)

Example 75 6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol

Following the procedure described in Example 58, using8-Methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (1.76 g, 6.59mmoL) as the starting material, the title compound was prepared as abrown solid

¹H NMR (CDCl₃) δ 8.21 (br, s, 1H), 7.32-6.78 (m, 8H), 4.12 (s, 2H).

MS (m/z): MH+, 254.

Example 76 5,11-dimethyl-5,11-dihydro-6H-indolo[3,2-c]quinolin-8-ol

Following the procedure described in Example 58, using8-methoxy-5,11-dimethyl-5,11-dihydro-6H-indolo[3,2-c]quinoline (410 mg)as the starting material, the title compounds was prepared as a brownsolid.

¹H NMR (CDCl₃) δ 7.91-6.68 (m, 7H), 3.13 (s, 2H), 2.95 (s, 3H)

Example 77 6,7-Dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulen-9-ol

Following the procedure described in Example 58, using9-methoxy-6,7-dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulene (520 mg) asthe starting material, the title compounds was prepared as a brownsolid.

MS (m/z): MNa⁺ (290), MH⁻ (266)

Example 78 9-methoxy-12H-5-thia-12-aza-dibenzo[a,e]azulene

9-Methoxy-6,7-dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulene (57 mg,0.203 mmoL) in DMF (2 mL) was treated with KO₂ (58 mg, 0.811 mmoL) and18-Crown-6 (54 mg, 0.203) and the reaction mixture was stirred at roomtemperature for 6 hours. Water was added to quench the reaction. Themixture was then partitioned between EtOAc and saturated NH₄Cl. Theaqueous phase was extracted two times with EtOAc. The organic layer fromeach extraction was combined, washed with water, brine, dried overanhydrous Na₂SO₄, filtered and concentrated to yield a brown oil. Thecrude material (the oil) was then purified by column chromatography(silica gel, 1:1 hexanes:EtOAc as eluent) to yield the title compound asa brown solid.

¹H NMR (CDCl₃) 8.05 (br, s, 1H), δ 8.02˜6.88 (m, 9H), 3.92 (s, 3H)

MS (m/z): MH+, 280.

Example 79 Trifluoro-methanesulfonic acid,11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-yl ester

A mixture of 11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluororen-8-ol(780 mg, 2.90 mmol), Tf₂O (900 mg, 3.19 mmol, 1.1 eq.), and Et₃N (0.506mL, 4.35 mmol, 1.5 eq.) in CH₂Cl₂ (10 mL) was stirred at 25° C. Thereaction mixture was quenched with aqueous saturated NaHCO₃. The organiclayer was washed with brine, dried, concentrated and purified by silicagel column (Hexane: EtOAc=4:1) to yield the title compound as a whitesolid.

¹H NMR (CDCl₃) δ 7.64-7.08 (m, 7H), 4.02 (s, 2H), 3.95 (s, 3H)

Example 80 acetic acid11-methyl-6,11-dihydro-5-thia-aza-benzo[a]fluoren-8-yl ester

Acetyl chloride (11 mg, 0.14 mmol, 1.1 eq.) was added dropwise to amixture of 8-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol (35mg, 0.13 mmol) and Et₃N (28 μl, 0.2 mmol, 1.5 eq.) in CH₂Cl₂ (2 mL) at0° C. The mixture was stirred at 0° C. for 2 hours and then warmed to25° C. After being warmed, the reaction mixture was quenched by aqueoussaturated NaHCO₃ solution. The organic layer was dried, concentrated andpurified (silica gel column, 3:1 Hexane/EtOAc) to yield the titlecompound as a white solid.

MS (m/z): MNa⁺ (346)

¹H NMR (CDCl₃) δ 7.59-6.95 (m, 7H), 4.03 (s, 2H), 3.94 (s, 3H), 2.32 (s,3H)

Example 81 Methanesulfonic acid11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-yl ester

A mixture of 8-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol(35 mg, 0.131 mmol), CH₃SO₂Cl (15 μL, 0.197 mmol, 1.5 eq.), pyridine (20mg, 0.262 mmol, 2.0 eq.) in CH₂Cl₂ (1 mL) was stirred at 25° C. for 2hours. The mixture was then partitioned between CH₂Cl₂ and saturatedNaHCO₃ aqueous solution. The aqueous layer was extracted three timeswith CH₂Cl₂. The combined organic layer was washed with brine, driedover anhydrous Na₂SO₄, filtered and concentrated to yield crudematerial. The crude material was purified by chromatography to yield thetitle compound as a white solid.

¹H NMR (CDCl₃) δ 7.66˜7.14 (m, 6H), 4.05 (s, 2H), 3.98 (s, 3H), 3.12 (s,3H)

Example 82 1,1,2,2,3,3,4,4,4-nonafluoro-butane-1-sulfonic acid11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-yl ester

To a solution of8-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol (180 mg, 0.711mmol) in CH₂Cl₂ (20 mL), Et₃N (129 μL, 0.924 mmol) was added dropwisefollowed by CF₃(CF₂)₃SO₂F (153 μL, 0.853 mmol) at 0° C. The reactionmixture was slowly warmed up to 25° C. over 2 hours. Then CH₂Cl₂, water,and saturated aqueous NaHCO₃ solution were added to the mixture. Theaqueous layer was extracted with CH₂Cl₂ and the organic layers werewashed with brine, dried, and concentrated. Flash chromatographypurification (12% EtOAc/Hexane) was used to yield the title as a whitesolid.

¹H NMR (CDCl₃) δ 7.61˜7.14 (m, 7H), 4.05 (s, 2H), 3.98 (s, 3H)

Example 83 2,2-dimethyl-propionic acid11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-yl ester

Following the procedure in Example 80, using11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol (105 mg, 0.393mmol) and PivCl (71 mg, 0.59 mmol) as the starting material, the titlecompound was prepared as a white solid.

MS (m/z): MH⁺ (352)

¹H NMR (CDOD₃) δ 7.65-6.91 (m, 7H), 4.05 (s, 2H), 3.96 (s, 3H), 1.40 (s,9H)

Example 848-(tert-butyl-dimethyl-silanyloxy)-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

Following the procedure described in Example 80, using11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol (1.15 g, 3.123mmol) and TBSCl (562 mg, 3.75 mmol) as the starting material, the titlecompound was prepared as a white solid.

MS (m/z): MH+ (382)

¹H NMR (CDCl₃) δ 7.50-6.78 (m, 7H), 3.92 (s, 2H), 3.75 (s, 3H), 1.05 (s,9H), 0.18 (s, 6H)

Example 858-(tert-butyl-dimethyl-silanyloxy)-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol (820 mg, 3.24 mmoL) inDMF (10 mL) was treated with imidazole (331 mg, 4.862 mmoL) followed byTBSCl (733 mg, 4.862 mmoL) at room temperature. The reaction was stirredfor 2 hours. The reaction mixture was then partitioned between CH₂Cl₂and water. The organic layer was washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated to yield a brown oil. The crudematerial (the oil) was then purified by column chromatography (silicagel, hexanes:EtOAc 4:1 as eluent) to yield the title compound as a brownsolid.

¹H NMR (CDCl₃) δ 8.58 (br, s, 1H), 7.35˜6.75 (m, 7H), 4.18 (s, 2H), 1.09(s, 9H), 0.23 (s, 6H).

MS (m/z): MH+, 368.

Example 86 2,2-dimethyl-propionic acid6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-yl-ester

6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol (1.01 g, 3.99 mmoL) inCH₂Cl₂ (5 mL) was treated with pyridine (0.387 mL, 4.788 mmoL) followedby PivCl (0.541 mL, 4.389 mmoL) at 0° C. The reaction mixture was slowlywarmed to room temperature over 2 hours. The reaction mixture was thenpartitioned between CH₂Cl₂ and saturated NH₄Cl. The aqueous phase wasextracted two times with CH₂Cl₂. The organic layer from each extractionwas combined, washed with water, brine, dried over anhydrous Na₂SO₄,filtered and concentrated to yield a brown oil. The crude material (theoil) was then purified by column chromatography (silica gel,hexanes:EtOAc 4:1 as eluent) to yield the title compound as a pale foam.

¹H NMR (CDCl₃) δ 8.45 (br, s, 1H), 7.35˜6.72 m, 7H), 4.10 (s, 2H), 1.35(s, 9H).

MS (m/z): MH+, 338.

Example 879-(tert-Butyl-dimethyl-silanyloxy)-6,7-dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulene

Following the procedure described in Example 80, using6,7-Dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulen-9-ol (350 mg, 1.31mmol) and TBSCl (225 mg, 1.50 mmol) as the starting material, the titlecompound was prepared as a white solid.

MS (m/z): MH+ (382)

Example 883,8-bis-(tert-butyl-dimethyl-silanyloxy)-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene

6,11-dihydro-5-thia-11-aza-benzo[a]fluorene-3,8-diol (298 mg, 1.11 mmoL)in DMF (5 mL) was treated with imidazole (188 mg, 2.77 mmoL) followed byTBSCl (417 mg, 2.77 mmoL) at room temperature. The reaction was stirredfor 2 hours. The reaction mixture was then partitioned between CH₂Cl₂and water. The organic layer was washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated to yield a brown oil. The crudematerial (the oil) was then purified by column chromatography (silicagel, hexanes:EtOAc 3:1 as eluent) to yield the title compound as a brownsolid.

¹H NMR (CDCl₃) δ 7.85 (br, s, 1H), 7.08˜6.35 (m, 6H), 3.98 (s, 2H) 0.85(s, 9H), 0.81 (s, 9H), 0.08 (s, 6H), 0.06 (s, 6H).

MS (m/z): MNa+, 520, MH−, 496.

Example 89[2-(8-methoxy-6H-5-thia-11-aza-benzo[a]fluoren-11-yl)-ethyl]-dimethyl-amine

The title compound was prepared from8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluoroene (1.50 g, 5.62mmol) and ClCH₂CH₂N(Me)₂ (620 mg, 5.80 mmol) were reacted according tothe procedure described in Example 19, wherein the procedure wasslightly modified, by addition of a catalytic amount of KI˜50 mg. Inthis way, the title compound was prepared as a brown solid.

¹H NMR (CDCl₃) δ 7.63-6.88 (m, 7H), 4.36 (t, 2H, J=6.6 Hz), 4.01 (s,2H), 3.83 (s, 3H), 2.72 (t, 2H, J=6.6 Hz), 2.31 (s, 6H)

MS (m/z): MH⁺ (339)

Example 9011-methyl-6,11-dihydro-5-thia-aza-benzo[a]fluorene-8-carbonitrile

A mixture of8-bromo-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (270 mg),as prepared in Example 57, and CuCN (270 mg) in DMF (25 ml) was refluxovernight at 170° C. The reaction mixture was filtered through a pad ofCelite and then partitioned between saturated NaHCO₃ aqueous solutionand EtOAc. The aqueous layer was extracted with EtOAc, the organiclayers were dried and concentrated to yield crude product. The crudeproduct was purified by chromatography (Hexane:ethyl acetate=5:1) toyield the title compound as a white solid.

¹H NMR (CDCl₃) δ 7.90 (s, 1H), 7.65-7.25 (m, 6H), 4.08 (s, 2H), 3.98 (t,3H)

MS (m/z): MH+ (277)

Example 9111-methyl-6,11,dihydro-5-thia-aza-benzo[a]fluorene-8-carboxylic acid

6,11-dihydro-5-thia-11-aza-benzo[a]fluorene-3,8-diol (1 mmol, 330 mg),as prepared in Example 31, in THF (15 ml) was treated with n-BuLi (2.0M, 0.6 ml, 1.2 mmol) at −78° C. for 30 minutes. Dry ice (1 equiv.) wasthen added to the reaction mixture at −78° C. After slowly warming thereaction mixture to room temperature, the reaction mixture was quenchedby saturated ammonium chloride, extracted by ethyl acetate, and purifiedby chromatography (Hexane:ethyl acetate=1:1) to yield the title compoundas a white solid.

¹H NMR (CDCl₃) δ 8.50 (s, 1H), 8.05-7.20 (m, 7H), 4.15 (s, 2H), 4.00 (s,3H)

MS (m/z): MH+ (296)

Example 9211-methyl-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene-8-carboxylic acid

n-BuLi was added dropwise into8-bromo-11-methyl-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (420 mg,1.338 mmoL) in THF (5 mL) at −78° C. After an additional 30 minutes, thereaction mixture was transferred into dry ice (˜10 g). The reactionmixture was then slowly warmed to room temperature. The solvent wasremoved and the residue was partitioned between EtOAc and 1 N NaOHsolution. The aqueous layer was then acidified to a pH of about 2 using1N HCl and extracted three times with EtOAc. The organic phase of eachextraction was combined, washed with water, brine, dried over anhydrousNa₂SO₄, filtered and concentrated to yield a clear oil. The oil was thenpurified by column chromatography (silica gel, hexanes:EtOAc 1:1 aseluent) to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 7.55˜6.68 (m, 7H), 5.30 (s, 2H), 3.88 (s, 3H).

MS (m/z): MH+, 280.

Example 9311-Methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene-8-carboxylic acidmethyl ester

6,11-dihydro-5-thia-11-aza-benzo[a]fluorene-3,8-diol (1 mmol, 330 mg),as prepared in Example 31, in THF (15 ml) was treated with n-BuLi (2.0M, 0.6 ml, 1.2 mmol) at −78° C. for 30 minutes, then methylchloroformate (1 equivalent) was added drop by drop to the reactionmixture at −78° C. After slowly warming up to room temperature, thereaction mixture was quenched by saturated ammonium chloride, extractedby ethyl acetate and purified by chromatography (Hexane:ethylacetate=5:1) to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 8.35 (s, 1H), 7.95-7.15 (m, 7H), 4.11 (s, 2H), 3.95 (s,3H), 4.00 (s, 3H)

MS (m/z): MH+ (309)

Example 948-methoxy-11-methyl-6,11-dihydro-5-oxa-4,11-diaza-benzo[a]fluoren-6-ol

To a mixture of8-methoxy-11-methyl-6,11-dihydro-5-oxa-4,11-diaza-benzo[a]fluorene (500mg, 1.887 mmol) in CH₃CN (15 mL) was added AlCl₃ (378 mg, 1.5 eq.).After 60 hours at 25° C., the mixture was quenched with saturatedNaHCO₃. The aqueous layer was extracted with EtOAc. The organic layerswere dried and concentrated to yield the title compound as a brownsolid.

MS (m/z): MH⁺ (282), MNa⁺ (304), MH⁻ (280)

¹H NMR (CDCl₃) δ 9.58 (s, 1H), 7.81-6.94 (m, 7H), 5.96 (br s, 1H), 3.87(s, 3H), 3.62 (s, 3H).

Example 951-[8(tert-butyl-dimethyl-silanyloxy)-6H-5-thia-11-aza-benzo[a]fluoren-11-yl]-ethanone

8-(tert-Butyl-dimethyl-silanyloxy)-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene(170 mg, 0.462 mmoL) in DMF (2 mL) was treated with NaH (60%, 37 mg,0.925 mmoL) at 0° C. Acetyl chloride (52 mg, 0.693 mmoL) was addeddropwise into the reaction 30 minutes later. The reaction mixture wasthan slowly warmed to room temperature over 2 hours. The reaction wasquenched with saturated NH₄Cl. The residue was partitioned betweenCH₂Cl₂ and saturated NaHCO₃. The aqueous phase was extracted two timeswith CH₂Cl₂. The organic layer from each extraction was combined, washedwith water, brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to yield a brown oil. The oil was then purified by columnchromatography (silica gel, hexanes:EtOAc 5:1 as eluent) to yield thetitle compound as a pale solid.

¹H NMR (CDCl₃) δ 7.88˜6.62 (m, 7H), 3.70 (s, 2H), 2.15 (s, 3H), 0.81 (s,9H), 0.05 (s, 6H).

MS (m/z): MH+, 410, MNa+, 432.

Example 96 1-(8-hydroxy-6H-5-thia-11-aza-benzo[a]fluoren-11-yl)ethan-one

1-[8(tert-butyl-dimethyl-silanyloxy)-6H-5-thia-11-aza-benzo[a]fluoren-11-yl]-ethanone(136 mg, 0.332 mmol) in THF (5 mL) was added TBAF (332 μL, 1.0 N in THF,0.332 mmol, 1.0 eq.). After 1 hour at 25° C., the reaction mixture waspartitioned between saturated NaHCO₃ aqueous solution and CH₂Cl₂, theaqueous layer was extracted with CH₂Cl₂ and the organic layers weredried and concentrated to yield crude product. The crude product waspurified by chromatography to yield the title compound as a yellowsolid.

MS (m/z): MH⁺ (296), MH⁻ (294)

¹H NMR (CDCl₃) δ 8.31 (s, 1H), 7.42-6.96 (m, 7H), 4.14 (s, 2H), 2.34 (s,3H)

Example 97 Acetic acid4-(8-methoxy-6H-5-oxa-11-aza-benzo[a]fluorene-11-carbonyl)-phenyl ester

A solution of 4-acetoxy-benzoic acid (108 mg, 0.598 mmoL) in CH₂Cl₂ (5mL) was treated with (COCl)₂ (0.07 mL, 0.796 mmoL) and 1 drop, acatalytic amount, of DMF at 0° C. The reaction mixture was slowly warmedto room temperature. The CH₂Cl₂ was removed and dried in vacuo. The4-acetoxy-benzoic acyl chloride in THF (2 mL) was treated with theindole-8-Methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (100 mg,0.398 mmoL) followed by Et₃N (0.796 mmoL, 0.11 mL) at 0° C. The reactionwas slowly warmed to room temperature over 2 hours. THF was removed invacuo. The residue was partitioned between CH₂Cl₂ and saturated NaHCO₃.The aqueous phase was extracted two times with CH₂Cl₂. The organiclayers from the two extractions were combined, washed with water andbrine, dried over anhydrous Na₂SO₄, filtered and concentrated to yield abrown oil. The crude material (the oil) was then purified by columnchromatography (silica gel, hexanes:EtOAc 4:1 as eluent) to yield thetitle compound as a pale solid.

¹H NMR (CDCl₃) δ 8.02˜6.75 (m, 11H), 5.52 (s, 2H), 3.98 (s, 3H), 2.55(s, 3H).

MS (m/z): MH+, 414.

Example 98 1-(8-methoxy-6H-5-oxa-11-aza-benzo[a]fluoren-11-yl)-ethanone

Acetyl chloride (0.064 mL, 0.896 mmoL) in CH₂Cl₂ (2 mL) was treated with8-methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (150 mg, 0.598mmoL) followed by Et₃N (0.896 mmoL, 0.125 mL) at 0° C. The reactionmixture was then slowly warmed to room temperature over 2 hours. Thereaction mixture was then partitioned between CH₂Cl₂ and saturatedNaHCO₃. The aqueous phase was extracted two times with CH₂Cl₂. Theorganic layers from the two extractions were then combined, washed withwater and brine, dried over anhydrous Na₂SO₄, filtered and concentratedto yield a brown oil. The crude material was then purified by columnchromatography (silica gel, hexanes:EtOAc 3:1 as eluent) to yield thetitle compound as a pale solid.

¹H NMR (CDCl₃) δ 7.98˜6.80 (m, 7H), 5.25 (s, 2H), 3.88 (s, 3H), 2.58 (s,2H).

MS (m/z): MH+, 294.

Example 9911-(4-benzyloxy-benzyl)-8-methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene

To a mixture of 8-methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene(100 mg, 0.398 mmoL) in DMF (2 mL) was added NaH (60%, 24 mg, 0.598mmoL) at 0° C. After 10 minutes, benzyl chloride (139 mg, 0.598 mmoL)was added dropwise into the reaction mixture at 0° C. The reactionmixture was slowly warmed to room temperature over 2 hours. The reactionmixture was then partitioned between EtOAc and saturated NH₄Cl. Theaqueous phase was extracted two times with EtOAc. The organic layersfrom the two extractions were combined, washed with water, brine, driedover anhydrous Na₂SO₄, filtered and concentrated to yield a brown oil.The oil was then purified by column chromatography (silica gel,hexanes:EtOAc 4:1 as eluent) to yield the title compound as a palesolid.

¹H NMR (CDCl₃) δ 7.40˜6.78 (m, 16H), 5.08 (s, 4H), 5.02 (s, 2H), 4.55(s, 2H), 3.88 (s, 3H).

MS (m/z): MH+, 448, MNa+, 470.

Example 10011-[4-(2-chloro-ethoxy)-benzyl]-8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorineand6a-[4-(2-chloro-ethoxy)-benzyl]-8-methoxy-6.6a-dihydro-5-thia-11-aza-benzo[a]fluorine

NaH (60%, 86 mg, 2.14 mmoL) was added into8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorine (520 mg, 1.95mmoL) in DMF (10 mL) at 0° C. After 10 minutes, the benzyl chloride (487mg, 1.95 mmoL) was added dropwise into the reaction at 0° C. Thereaction mixture was slowly warmed to room temperature over 2 hours. Thereaction mixture was then partitioned between EtOAc and saturated NH₄Cl.The aqueous phase was extracted two times with EtOAc. The organic layersfrom the two extractions were combined, washed with water, brine, driedover anhydrous Na₂SO₄, filtered and concentrated to yield a brown oil.The crude material (the oil) was then purified by column chromatography(silica gel, hexanes:EtOAc 4:1 as eluent) to yield the both products asyellow solids.

11-[4-(2-chloro-ethoxy)-benzyl]-8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorine

¹H NMR (CDCl₃) δ 7.50˜6.82 (m, 11H), 5.41 (s, 2H), 4.23 (t, J=10.5 Hz,2H), 4.12 (s, 2H), 3.88 (s, 3H), 3.82 (t, J=10.5 Hz, 2H).

MS (m/z): MH+, 436.

6a-[4-(2-chloro-ethoxy)-benzyl]-8-methoxy-6,6a-dihydro-5-thia-11-aza-benzo[a]fluorine

¹H NMR (CDCl₃) δ 8.06˜6.45 (m, 11H), 4.15 (abq, J=8.5 Hz, 2H), 3.85 (t,J=8.0 Hz, 2H), 3.80 (s, 3H), 3.32 (abq, J=12.5 Hz, 1H), 3.28 (t, J=8.0Hz, 2H), 2.90 (abq, J=12.5 Hz, 1H).

MS (m/z): MH+, 436.

Example 101(8-methoxy-5H-6-thia-11-aza-benzo[s]fluoren-11-yl)-[4-(2-piperdin-1-yl-ethoxy)-phenyl]-methanone

4-(2-Piperidin-1-yl-ethoxy)-benzoic acid (231 mg, 0.808 mmoL) wasdissolved in THF (2 mL). SOCl₂ (0.08 mL, 1.01 mmoL) was added into thereaction at room temperature. The reaction mixture was then heated at50° C. until it turned clear. THF was then removed and the acyl chloridewas dried in vacuo. The8-methoxy-5,11-dihydro-6-thia-11-aza-benzo[a]fluorine (180 mg, 0.673mmoL) in DMF (5 mL) was treated with NaH (60%, 0.076 mg, 1.884 mmoL) oneportion at 0° C. After addition of NaH, the reaction mixture was stirredfor additional 10 minutes. 4-(2-Piperidin-1-yl-ethoxy)-benzoic acylchloride in DMF (2 mL) was added into the reaction mixture. The reactionwas then slowly warmed to room temperature. Water and CH₂Cl₂ were addedand the aqueous layer was exacted three times with CH₂Cl₂. The organiclayer from each extraction was combined, washed with water, brine, driedover anhydrous Na₂SO₄, filtered and concentrated to yield a brown oil.The oil was then purified by column chromatography (silica gel, CH₂Cl₂:MeOH 6:1 as eluent) to yield the title compound as a colorless oil.

¹H NMR (CDCl₃) δ 8.05˜6.78 (m, 11H), 4.20 (t, J=10.5 Hz, 2H), 4.02 (s,2H), 3.95 (s, 3H), 2.90 (t, J=10.5 Hz, 2H0, 2.60 (m, 4H), 1.68 (m, 4H0,1.50 (m, 2H).

MS (m/z): MH+, 499.

Example 102{2-[4-(7-benzyloxy-3-methoxy-benzo[4,5]furo[3,2-b]indol-10-ylmethyl)-phenoxy]-ethyl}-diethyl-amine

To a mixture of 7-benzyloxy-3-methoxy-10H-benzo[4,5]furo[3,2-b]indole(102 mg, 0.297 mmol) in DMF (5 mL) was added NaH (37 mg, 60% in mineraloil, 3.0 eq.) followed by[2-(4-chloromethyl-phenoxy)-ethyl]-diethyl-amine hydrochloride salt (99mg, 0.356 mmol) at 0° C. The mixture was stirred at 0° C. for 30minutes, warmed to 25° C., and quenched by NH₄Cl (solid). EtOAc andwater were then added to the mixture. The reaction mixture was thenpartitioned between EtOAc and water. The aqueous layer was extractedthree times with EtOAc. The combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated to yieldcrude material. The crude material was purified by silica gel (EtOAc toCH₂Cl₂: MeOH 5:1) to yield the title compound as a brown solid.

MS (m/z): MH⁺ (549)

¹H NMR (CDCl₃) δ 7.48-6.78 (m, 15H), 5.46 (s, 2H), 5.12 (s, 2H), 3.98(t, 2H, J=6.6 Hz), 3.88 (s, 3H), 2.82 (t, 2H, J=6.6 Hz), 2.60 (q, 4H,J=6.7 Hz), 1.05 (t, 6H)

Example 103Diethyl-{2-[4-(8-methoxy-6H-5-oxa-benzo[a]fluoren-11-ylmethyl)-phenoxy]-ethyl}-amine

Following the procedure described in Example 102, using8-methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (406 mg, 1.62 mmol)and [2-(4-chloromethyl-phenoxy)-ethyl]-diethyl-amine hydrochloride saltas the starting material, the title compound was prepared as a brownsolid.

MS (m/z): MH⁺ (457)

¹H NMR (CDCl₃) δ 7.28-6.80 (m, 7H), 5.48 (d, 2H, J=1.5 Hz), 3.97 (m,2H), 3.89 (s, 2H), 2.85 (q, 2H, J=6.5 Hz), 2.65 (m, 4H), 1.07 (m, 6H)

Example 1048-Methoxy-11-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene

Following the procedure described in Example 102, using8-methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (150 mg, 0.562mmol) and [2-(4-chloromethyl-phenoxy)-ethyl]-cyclohexanyl-aminehydrochloride salt as the starting material, the title compound wasprepared as a brown solid.

MS (m/z): MH⁻ (468)

Example 1056a-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-6.6a-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol

8-Methoxy-11-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene(93 mg, 0.192 mmoL) in CH₂Cl₂ (5 mL) was treated with EtSH (0.06 mL,0.768 mmoL) followed by AlCl₃ (128 mg, 0.959 mmoL) at room temperature.The reaction mixture was stirred at room temperature for 5 hours. Thereaction was then cooled to 0° C. and saturated NaHCO₃ was added toquench the reaction mixture. The residue was partitioned between CH₂Cl₂and water. The organic layer was washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated to yield a brown oil. The crudematerial (the oil) was then purified by column chromatography (silicagel, CH₂Cl₂: MeOH 4:1 as eluent) to yield the title compound as acolorless oil.

¹H NMR (CDCl₃) δ 7.90˜6.52 (m, 12H), 3.98 (t, J=8.5 Hz, 2H), 3.35 (abq,J=11.5 Hz, 2H), 3.10 (abq, J=10.5 Hz, 2H), 2.75 (t, J=8.5 Hz, 2H), 2.65(m, 4H), 1.60 (m, 4H), 1.45 (m, 2H).

MS (m/z): MH+, 471.

Example 10610-[4-(2-diethylamino-ethoxy)-benzyl]-3-methoxy-10H-benzo[4,5]furo[3,2-b]indol-7-ol

A mixture of{2-[4-(7-benzyloxy-3-methoxy-benzo[4,5]furo[3,2-b]indol-10-ylmethyl)-phenoxy]-ethyl}-diethyl-amine(102 mg, 0.186 mmol) and 10% Pd/C (˜100 mg) in EtOH (10 mL) was stirredunder a H₂ balloon at 25° C. overnight. The solution was filtered,concentrated and purified to yield the title compound as a yellow solid.

MS (m/z): MH⁺ (459)

¹H NMR (CDCl₃) δ 7.18-6.54 (m, 10H), 5.22 (s, 2H), 4.01 (t, 2H, J=6.4Hz), 3.79 (s, 3H), 2.94 (t, 2H, J=6.4 Hz), 2.75 (q, 4H, J=6.4 Hz), 1.05(t, 6H, J=6.6 Hz)

Example 107diethyl-{2-[4-(3-methoxy-benzo[4,5]furo[3,2-b]indol-10-ylmethyl)-phenoxy]-ethyl}-amine

Following the procedure described in Example 102, using3-methoxy-10H-benzo[4,5]furo[3,2-b]indole (405 mg, 1.517 mmol) and[2-(4-chloromethyl-phenoxy)-ethyl]-diethyl-amine hydrochloride salt as astarting material, the title compound was prepared as a brown solid.

¹H NMR (CDCl₃) δ 7.54-6.78 (m, 11H), 5.40 (s, 2H), 4.04 (t, 2H, J=6.5Hz), 3.87 (s, 3H), 2.85 (t, 2H, J=6.6 Hz), 2.62 (q, 4H, J=6.6 Hz), 1.05(t, 6H, J=6.6 Hz)

Example 1089-methoxy-12-[4-(2-pyrrolidin-1-yl-ethoxy)-benzyl]-6,7-dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulene

Following the same procedure in Example 102, using9-methoxy-6,7-dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulene (562 mg) and[2-(4-chloromethyl-phenoxy)-ethyl]-cyclopentyl-amine hydrochloride saltas the starting material, the title compound was prepared as a brownsolid.

MS (m/z): MH⁺ (485)

¹H NMR (CDCl₃) δ 8.12-6.63 (m, 11H), 5.02 (s, 2H), 4.15 (t, 2H, J=6.5Hz), 3.48 (s, 3H), 3.38 (t, 2H, J=6.6 Hz), 3.23 (t, 2H, J=6.6 Hz), 2.83(t, 2H, J=6.6 Hz), 2.68 (broad s, 4H), 1.67 (m, 4H)

Example 1099-(tert-Butyl-dimethyl-silanyloxy)-12-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-6,7-dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulene

Following the same procedure in Example 102, using9-(tert-Butyl-dimethyl-silanyloxy)-6,7-dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulene(190 mg, 0.5 mmol) and[2-(4-chloromethyl-phenoxy)-ethyl]-cyclohexanyl-amine hydrochloride saltas the starting material, title compound was prepared as a brown solid.The compound was used in the next step without additional purification.

MS (m/z): MH⁺ (586)

Example 11012-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-6,7-dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulen-9-ol

9-(tert-Butyl-dimethyl-silanyloxy)-12-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-6,7-dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulene(130 mg, 0.222 mmol) in 5 mL 1.0 N TBAF in THF solution was stirred for30 min at room temperature. The reaction was worked up by CH₂Cl₂extraction three times from water. The combined organic layer was driedand concentrated and purified by column using 4:1 CH₂Cl₂ and methanolsolution to yield the title compound as a brown solid.

MS (m/z): MH⁺ (485), MH⁻ (483)

¹H NMR (CDCl₃) δ 8.12-8.18 (s, 1H), 7.58-6.61 (m, 11H), 4.40 (s, 1H),4.05 (m, 2H), 3.34 (t, 2H, J=6.6 Hz), 3.13 (m, 2H), 2.72 (m, 2H), 2.53(br s, 4H), 1.58 (br s, 4H), 1.39 (br m, 2H)

Example 113-methoxy-10-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-10H-benzo[4,5]furo[3,2-b]indole

Following the same procedure in Example 102, using8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (420 mg, 1.573mmol) and 1-[2-(4-chloromethyl-phenoxy)-ethyl]-piperidine (1.2 eq.) asthe starting material, the title compound was prepared as a brown solid.

MS (m/z): MH⁺ (485)

¹H NMR (CDCl₃) δ 7.52-6.76 (m, 11H), 5.38 (s, 2H), 4.13 (q, 2H, J=6.6.Hz), 3.84 (s, 3H), 2.78 (t, 2H, J=6.6 Hz), 2.55 (m, 4H), 1.64 (m, 4H),1.35 (m, 2H)

Example 112 2,2-dimethyl-propionic acid11-[4-(2-diethylamino-ethoxy)-benzyl]-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ylester

PivCl (15 uL, 0.120 mmol, 1.1 eq.) and pyridine (11 μL, 0.131 mmol, 1.2eq.) along with a few drops of DMF were added to a mixture of11-[4-2(diethylamino-ethoxy)-benzyl]-6,11-dihydro-5-thia-11-aza-benzo[a]fluren-8-ol(50 mg, 0.109 mmol) in CH₂Cl₂ (2 mL). The reaction mixture waspartitioned between saturated NaHCO₃ aqueous solution and CH₂Cl₂, theaqueous layer was extracted with CH₂Cl₂ and the organic layers weredried and concentrated to yield crude product. The crude product waspurified by flash chromatograph to yield the title compound as a brownsolid.

MS (m/z): MH⁺ (543), MH⁻ (541)

¹H NMR (CD₃OD) δ 7.44-6.74 (m, 11H), 5.41 (2H), 4.01 (t, 2H, J=6.5 Hz),3.29 (s, 2H), 2.86 (t, 2H, J=6.5 Hz), 2.62 (q, 4H, J=6.5 Hz), 1.38 (s,9H), 1.05 (t, J=6.8 Hz, 6H)

Example 1138-(tert-butyl-dimethyl-silanyloxy)-11-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-6,11-dihydro-5-thia-11-aza-benzo[a]fluorineand11-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol

NaH (60%, 144 mg, 1.317 mmoL) was added into8-(tert-butyl-dimethyl-silanyloxy)-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene(440 mg, 1.197 mmoL) in DMF (5 mL) at 0° C. After 10 minutes,1-[2-(4-chloromethyl-phenoxy)-ethyl]-piperidine (382 mg, 1.317 mmoL) wasadded dropwise into the reaction at 0° C. The reaction mixture wasslowly warmed to room temperature over 2 hours. The reaction mixture wasthen partitioned between EtOAc and saturated NH₄Cl. The aqueous phasewas extracted two times with EtOAc. The organic layers from the twoextractions were combined, washed with water, brine, dried overanhydrous Na₂SO₄, filtered and concentrated to yield a brown oil. Thecrude material (the oil) was then purified by column chromatography(silica gel, first EtOAc then CH₂Cl₂:MeOH 4:1 as eluent) to yield8-(tert-butyl-dimethyl-silanyloxy)-11-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-6,11-dihydro-5-thia-11-aza-benzo[a]fluorineas a pale foam and11-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-olas a yellow solid.

8-(tert-butyl-dimethyl-silanyloxy)-11-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-6,11-dihydro-5-thia-11-aza-benzo[a]fluorine

¹H NMR (CDCl₃) δ 7.28˜6.52 (m, 11H), 5.16 (s, 2H), 3.88 (t, J=10.2 Hz,2H), 2.55 (t, J=10.2 Hz, 2H), 2.31 (m, 4H), 1.41 (m, 4H), 1.22 (m, 2H),0.81 (s, 9H), 0.03 (s, 6H).

MS (m/z): MH+, 585, MNa+, 607.

11-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-6,11dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol

¹H NMR (CDCl₃) δ 7.42˜6.72 (m, 12H), 5.32 (s, 2H), 4.15 (t, J=10.5 Hz,2H), 4.05 (s, 2H0, 2.85 (t, J=10.5 Hz, 2H), 2.60 (m, 4H), 1.65 (m, 4H),1.44 (m, 2H).

MS (m/z): MH+, 471.

Example 114(2-{4-[8-(tert-Butyl-dimethyl-silanyloxy)-6H-5-thia-11-aza-benzo[a]fluoren-11-ylmethyl]-phenoxy}-ethyl)-diethyl-amineand11-[4-(2-Diethylamino-ethoxy)-benzyl]-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol

Following the procedure described in Example 113, using8-(tert-butyl-dimethyl-silanyloxy)-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene(490 mg, 1.33 mmoL) and [2-(4-chloromethyl-phenoxy)-ethyl]-diethyl-aminehydrochloride salt (370 mg, 1.33 mmoL) as the starting material,(2-{4-[8-(tert-Butyl-dimethyl-silanyloxy)-6H-5-thia-11-aza-benzo[a]fluoren-11-ylmethyl]-phenoxy}-ethyl)-diethyl-aminewas prepared as a pale foam and11-[4-(2-Diethylamino-ethoxy)-benzyl]-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-olwas prepared as a yellow solid.

(2-{4-[8-(tert-Butyl-dimethyl-silanyloxy)-6H-5-thia-11-aza-benzo[a]fluoren-11-ylmethyl]-phenoxy}-ethyl)-diethyl-amine

¹H NMR (CDCl₃) δ 7.25˜6.48 (m, 11H), 5.15 (s, 2H), 3.85 (t, J=8.5 Hz,2H), 3.84 (s, 2H), 2.73 (t, J=8.5 Hz, 2H), 2.45 (t, J=12.5 Hz, 2H), 0.88(t, J=12.5 Hz, 2H), 0.81 (s, 9H), 0.08 (s, 6H).

MS (m/z): MH+, 573.

11-[4-(2-Diethylamino-ethoxy)-benzyl]-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol

¹H NMR (CDCl₃) 7.45˜6.68 (m, 12H), 5.30 (s, 2H), 4.10 (t, J=10.5 Hz, 2H)4.05 (s, 2H) 2.98 (t, J=10.5 Hz, 2H), 2.70 (m, J=12.5 Hz, 4H), 1.12 (t,J=12.5 Hz, 6H).

MS (m/z): MH+, 459.

Example 115 2,2-dimethyl-propionic acid11-[4-(2-diethylamino-ethoxy)-benzyl]-6,11-dihydro-5-thia-aza-benzo[a]fluoren-8-ylester

11-[4-(2-Diethylamino-ethoxy)-benzyl]-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol(50 mg, 0.109 mmoL) in CH₂Cl₂ (1 mL) was treated with pyridine (0.011mL, 0.131 mmoL) followed by PivCl (0.015 mL, 0.120 mmoL) at 0° C. Thereaction mixture was slowly warmed to room temperature over 2 hours. Thereaction mixture was then partitioned between CH₂Cl₂ and saturatedNH₄Cl. The aqueous phase was extracted two times with CH₂Cl₂. Theorganic layer from each extraction was combined, washed with water,brine, dried over anhydrous Na₂SO₄, filtered and concentrated to yield abrown oil. The crude material (the oil) was then purified by columnchromatography (silica gel, CH₂Cl₂:MeOH 4:1 as eluent) to yield thetitle compound as a pale foam.

¹H NMR (CDCl₃) δ 7.52˜6.78 (m, 11H), 5.25 (s, 2H), 4.15 (t, J=10.5 Hz,2H), 4.00 (s, 2H), 2.85 (t, J=10.5 Hz, 2H), 2.60 (m, J=12.5 Hz, 4H),1.21 (s, 9H), 1.08 (t, J=12.5 Hz, 6H).

MS (m/z): MH+, 544.

Example 1168-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene5,5-dioxide

To a solution of8-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene in MeOH(3 mL) and H₂O (5 mL) was added OXONE (1.68 g, 2.74 mmol). The reactionmixture was stirred overnight at 25° C. The solvent was removed in vacuoand the residue was then partitioned between saturated NaHCO₃ aqueoussolution and CH₂Cl₂, the aqueous layer was extracted with CH₂Cl₂ and theorganic layers were dried and concentrated to yield crude product. Thecrude product was then purified by flash chromatography to yield thetitle compound as a white solid.

MS (m/z): MNa⁺ (336)

¹H NMR (CDCl₃) δ 8.13˜6.91 (m, 7H), 4.52 (s, 2H), 4.04 (s, 3H), 3.88 (s,3H)

Example 1178-(tert-butyl-dimethyl-silanyloxy)-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene5-oxide and11-methyl-5-oxo-6,11-dihydro-5H-5I4-thia-11-aza-benzo[a]fluoren-8-ol and8-(tert-butyl-dimethyl-silanyloxy)-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene5,5-dioxide

A mixture of8-(tert-Butyl-dimethyl-silanyloxy)-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene(490 mg, 1.286 mmol), as prepared in Example 45, and OXONE (791 mg,1.286 mmol) in MeOH (2 mL), H₂O (2 mL) and THF (2 mL) was stirred at 25°C. After the solvent was removed in vacuo, the residue was partitionedbetween saturated NaHCO₃ aqueous solution and CH₂Cl₂, the aqueous layerwas extracted with CH₂Cl₂ and the organic layers were dried andconcentrated to yield crude product. The crude product was purified bychromatography to yield8-(tert-butyl-dimethyl-silanyloxy)-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene5-oxide as a white solid,11-methyl-5-oxo-6,11-dihydro-5H-5I4-thia-11-aza-benzo[a]fluoren-8-ol asa pale solid, and8-(tert-butyl-dimethyl-silanyloxy)-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene5,5-dioxide as a white solid respectively.

8-(tert-butyl-dimethyl-silanyloxy)-11-methyl-6,1-dihydro-5-thia-11-aza-benzo[a]fluorene5-oxide

MS (m/z): MH⁺ (398), MNa⁺ (420)

¹H NMR (CDCl₃) δ 7.79-7.88 (m, 7H), 4.34 (d, 1H, J=13.2 Hz), 4.21 (d,1H, J=13.1 Hz), 3.89 (s, 3H), 1.04 (s, 9H), 0.21 (s, 6H)

11-methyl-5-oxo-6,11-dihydro-5H-5I4-thia-11-aza-benzo[a]fluoren-8-ol

MS (m/z): MNa⁺ (306), MH⁻ (282)

¹H NMR (CDCl₃) δ 8.04-6.85 (m, 7H), 4.57 (s, 2H), 4.03 (s, 3H).

8-(tert-butyl-dimethyl-silanyloxy)-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene5,5-dioxide

MS (m/z): MH⁺ (414), MNa⁺ (436)

¹H NMR (CDCl₃) δ 8.13-6.83 (m, 7H), 4.46 (s, 2H), 3.98 (s, 3H), 1.05 (s,9H), 0.22 (s, 6H)

Example 118 8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene5-oxide

8-Methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (79 mg, 0.281mmoL) in DMF (5 mL) was treated with KO-t-Bu (1.0 M in THF, 0.48 mL,0.48 mmoL) under a flow of O₂ for 6 hours. The reaction mixture was thenpartitioned between water and EtOAc. The EtOAc layer was washed withsaturated NH₄Cl, water, brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to yield a brown oil. The crude material (the oil) was thenpurified by column chromatography (silica gel, CH₂Cl₂: MeOH 9:1 aseluent) to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 8.21 (br, s, 1H0, 7.85˜6.88 (m, 7H), 4.25 (abq, J=10.5Hz, 2H), 3.85 (s, 3H).

MS (m/z): MH+, 284.

Example 1198-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene5,5-dioxide

8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (257 mg, 0.915mmoL) in MeOH (3 mL) and water (3 mL) was treated with OXONE (2.744mmoL, 1.68 g) at room temperature. The reaction mixture was stirred for6 hours. The solvent was removed and the residue was partitioned betweenEtOAc and saturated NaHCO₃. The aqueous phase was extracted two timeswith EtOAc. The organic layer from each extraction was combined, washedwith water, brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to yield a brown solid. The crude material (the oil) wasthen purified by column chromatography (silica gel, 1:1 hexanes:EtOAc aseluent) to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 8.10˜6.85 (m, 7H), 4.45 (s, 2H), 3.95 (s, 3H), 3.80 (s,3H).

MS (m/z): MH+, 314.

Example 12011-methyl-5,1-dioxo-6,11-dihydro-5H-5λ⁶-thia-11-aza-benzo[a]fluoren-8-ol

A mixture of sulfone8-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene5,5-dioxide (32 mg, 0.102 mmoL) and pyridine HCl salt (176 mg, 1.534mmoL) was heated to 180° C. in a sealed tube for 30 minutes. The residuewas dissolved in EtOAc. The reaction mixture was then filtrated througha pad of Celite to remove solids. The filtrate was partitioned betweenEtOAc and saturated NaHCO₃. The aqueous phase was extracted two timeswith EtOAc. The organic layer from each extraction was combined, washedwith water, brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to yield a brown solid. The crude material (the oil) wasthen purified by column chromatography (silica gel, 1:1 hexanes:EtOAc aseluent) to yield the title compound as a white solid.

¹H NMR (d-DMSO) δ 9.05 (s, 1H), 8.00˜6.82 (m, 7H, 4.82 (s, 2H), 4.05 (s,3H).

MS (m/z): MH+, 298.

Example 121 8-methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluoren-6-ol

8-methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (300 mg, 1.194mmoL) in DMF (5 mL) was treated with KO-t-Bu (1.0 M in THF, 2.0 mL, 2.0mmoL) under a flow of O₂ for 6 hours. The reaction mixture was thenpartitioned between water and EtOAc. The EtOAc layer was washed withsaturated NH₄Cl, water, brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to yield a brown oil. The crude material was then purifiedby column chromatography (silica gel, hexanes:EtOAc 9:1 as eluent) toyield the title compound as a white solid.

¹H NMR (CDCl₃) δ 9.90 (s, 1H), 9.75 (br, s, 1H), 7.82˜6.85 (m, 7H), 3.82(s, 3H).

MS (m/z): MH+, 268.

Example 1228-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene 5 oxide

A solution of8-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene 5-oxide(442 mg, 1.573 mmoL) in MeOH (3 mL) and water (3 mL) was treated withOXONE (1.573 mmoL, 967 mg) at room temperature. The reaction mixture wasthen stirred for 6 hours. The solvent was removed and the residue waspartitioned between EtOAc and saturated NaHCO₃. The aqueous phase wasextracted two times with EtOAc. The organic layer from the two exactionswas combined washed with water, brine, dried over anhydrous Na₂SO₄,filtered and concentrated to yield a brown solid. The crude material(the oil) was then purified by column chromatography (silica gel, 1:1hexanes:EtOAc as eluent) to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 7.98˜6.98 (m, 7H), 4.32 (abq, J=12.5 Hz, 2H), 4.00 (s,3H), 3.92 (s, 3H).

MS (m/z): MH+, 298, MNa+, 320.

Example 123 2,3-Dihydro-thiopyrano[2,3-b]pyridin-4-one

Following the procedure described in Da Settimo, Antonio; Marini, AnnaMaria; Primofiore, Giampaolo; Da Settimo, Federico; Salerno, Silvia; LaMotta, Concettina; Pardi, Gianluca; Ferrarini, Pier Luigi; Mori, ClaudioJournal of Heterocyclic Chemistry 2000, 37, 379-382, the title compoundwas prepared as a colorless oil.

Example 124 8-methoxy-6,11-dihydro-5-thia-4,11-diaza-benzo[a]fluorene

A mixture of 2,3-dihydro-thiopyrano[2,3-b]pyridin-4-one (2.24 g, 13.6mmoL) and 4-methoxy-phenylhydrazine HCl salt (2.60 g, 14.9 mmoL) in EtOH(10 mL) was refluxed for 5 hours. The reaction mixture was cooled andfiltrated through a pad of Celite to remove any solids in the mixture.The solvent was removed in vacuo. The remaining residue was partitionedbetween EtOAc and saturated NaHCO₃. The aqueous phase was extracted twotimes with EtOAc. The organic layer of each extraction was washed withwater, brine, dried over anhydrous Na₂SO₄, filtered and concentrated toyield a brown oil. The crude material (the oil) was then purified bycolumn chromatography (silica gel, hexanes:EtOAc1:1 as eluent) to yieldthe title compound as a pale solid.

¹H NMR (CDCl₃) δ 8.05 (br, s, 1H), 7.20˜6.55 (m, 7H), 3.78 (s, 2H), 3.60(s, 3H).

MS (m/z): MH+, 269.

Example 1258-methoxy-11-methyl-6,11-dihydro-5-thia-4,11-diaza-benzo[a]fluorene

NaH (60%, 41 mg, 1.03 mmoL) was added into8-methoxy-6,11-dihydro-5-thia-4,11-diaza-benzo[a]fluorene (250 mg, 0.933mmoL) in DMF (3 mL) at 0° C. After 10 minutes, MeI (0.064 mL, 0.93 mmoL)was added dropwise into the reaction at 0° C. The reaction mixture wasslowly warmed to room temperature over 2 hours. The reaction mixture wasthen partitioned between EtOAc and saturated NH₄Cl. The aqueous phasewas extracted two times with EtOAc. The organic layer from eachextraction was combined, washed with water, brine, dried over anhydrousNa₂SO₄, filtered and concentrated to yield a brown oil. The crudematerial (the oil) was then purified by column chromatography (silicagel, hexanes:EtOAc 1:1 as eluent) to yield the title compound as a whitesolid.

¹H NMR (CDCl₃) δ 8.25˜6.95 (m, 6H), 4.21 (s, 2H), 3.90 (s, 3H), 3.86 (s,3H).

MS (m/z): MH+, 283.

Example 12611-Methyl-6,11-dihydro-5-thia-4,11-diaza-benzo[a]fluoren-8-ol

A mixture of8-methoxy-11-methyl-6,11-dihydro-5-thia-4,11-diaza-benzo[a]fluorene (100mg, 0.355 mmoL) and pyridine HCl salt (410 mg, 3.55 mmoL) was sealed ina tube and heated to 180° C. for 2 hours. The reaction mixture wascooled and the residue was partitioned between water and EtOAc. TheEtOAc layer was washed with saturated NaHCO₃, water, brine, dried overanhydrous Na₂SO₄, filtered and concentrated to yield a brown oil. Thecrude material (the oil) was then purified by column chromatography(silica gel, hexanes:EtOAc 1:1 as eluent) to yield the title compound asa white solid.

¹H NMR (CDCl₃) δ 8.28˜6.80 (m, 7H), 4.18 (s, 2H), 3.85 (s, 3H).

MS (m/z): MH+, 269.

Example 127 1-Methyl-1,5,6,7-tetrahydro-indazol-4-one

Following the procedure described in Schenone, Pietro; Mosti, Luisa;Menozzi, Giulia Journal of Heterocyclic Chemistry 1982, 19, 1355-61, thetitle compound was prepared as a colorless oil.

Example 1287-Methoxy-3-methyl-3,4,5,10-tetrahydro-2,3,10-triaza-cyclopenta[a]fluorene

Following the procedure described in Example 124, using (2.54 g) as thestarting material, the title compound was prepared as a white solid.

MS (m/z): MH⁺ (254)

Example 1297-methoxy-3,10-dimethyl-3,4,5,10-tetrahydro-2,3,10-triaza-cyclopenta[a]fluorene

Following the procedure described in Example 125, using7-methoxy-3,-methyl-3,4,5,10-tetrahydro-2,3,10-triaza-cyclopenta[a]fluorene(260 mg, 1.03 mmol) as the starting material, the title compound wasprepared as a white solid.

MS (m/z): MH⁺ (268)

¹H NMR (DMSO-d₆) δ 7.71-6.59 (m, 4H), 3.79 (s, 3H), 3.75 (s, 3H), 3.72(s, 3H), 2.89 (m, 4H)

Example 1307-methoxy-3,10-dimethyl-3,10-dihydro-2,3,10-triaza-cyclopenta[a]fluorene

7-methoxy-3,10-dimethyl-3,4,5,10-tetrahydro-2,3,10-triaza-cyclopenta[a]fluorene(136 mg, 0.51 mmol) in DMF (2 mL) was treated with KO₂ (5.0 eq.) at roomtemperature. The reaction mixture was stirred overnight. Water was addedand the reaction mixture was extracted with ethyl acetate. The organiclayer was washed with brine and dried, concentrated. The crude materialwas purified by silica gel column to yield the title compound as a whitesolid.

MS (m/z): MH⁺ (266)

¹H NMR (CDCl₃) δ 8.32-7.09 (m, 6H), 4.18 (s, 6H), 3.96 (s, 3H)

Example 1313,10-dimethyl-3,10-dihydro-2,3,10-triaza-cyclopenta[a]fluoren-7-ol

A mixture of7-methoxy-3,10-dimethyl-3,10-dihydro-2,3,10-triaza-cyclopenta[a]fluorene(55 mg, 0.21 mmol), AlCl₃ (0.84 mmol, 4.0 eq.) and EtSH (0.63 mmol, 3.0eq.) in CH₂Cl₂ (2 mL) was stirred at room temperature for 16 hours. Thereaction mixture was poured into cold saturated NaHCO₃ solution,extracted with CH₂Cl₂, washed with brine and dried, concentrated toyield the crude product. The crude product was then purified bychromatography to yield the title compound as a white solid.

MS (m/z): MH⁺ (252)

Example 132 7,8-Dihydro-6H-quinolin-5-one

Following the procedure described in Albright, J. Donald; Du, XuemeiJournal of Heterocyclic Chemistry 2000, 37, 41-46, the title compoundwas prepared as a colorless oil.

Example 133 8-methoxy-5,11-dihydro-6H-pyrido[3,2-a]carbazole

Following the procedure described in Example 124, using7,8-dihydro-6H-quinolin-5-one (860 mg, 6.0 mmol) as the startingmaterial, the title compound was prepared as a brown solid.

¹H NMR (CDCl₃) δ 8.20-6.75 (m, 6H), 3.80 (s, 3H), 3.15 (t, J=3.0 Hz,2H). 3.05 (t, J=3.0 Hz, 2H)

MS (m/z): MH+ (251)

Example 134 8-methoxy-11-methyl-5,11-dihydro-6H-pyrido[3,2-a]carbazole

Following the procedure described in Example 125, using8-methoxy-5,11-dihydro-6H-pyrido[3,2-a]carbazole (1.25 g, 5.0 mmol), asprepared in Example 133, as the starting material, the title compoundwas prepared as a white solid.

¹H NMR (CDCl₃) δ 8.35-6.85 (m, 6H), 3.90 (s, 3H), 3.85 (s, 3H), 3.20 (t,J=3.0 Hz, 2H). 3.00 (t, J=3.0 Hz, 2H)

MS (m/z): MH+ (265)

Example 135 11-methyl-5,11-dihydro-6H-pyrido[3,2-a]carbazol-8-ol

Following the procedure described in Example 126, using8-methoxy-11-methyl-5,11-dihydro-6H-pyrido[3,2-a]carbazole (0.8 g) asthe starting the material, the title compound was prepared as a brownsolid,

¹H NMR (CDCl₃) δ 8.38-6.83 (m, 6H), 3.92 (s, 3H), 3.22 (t, 2H, J=6.7Hz), 2.93 (t, 2H, J=6.7 Hz)

MS (m/z): MH+ (250)

Example 136 7,8-Dihydro-6H-quinoxalin-5-one

Following the procedure described in Chow, Ken; Gil, Daniel W.; Burke,James A.; Harcourt, Dale A.; Garst, Michael E.; Wheeler, Larry A.; Munk,Stephen A. PCT Int. Appl. WO 9928300 A1 19990610, the title compound wasprepared as a colorless oil.

Example 137 8-methoxy-5,11-dihydro-6H-pyrazino[2,3-a]carbazole

Following the procedure described in Example 124, using7,8-dihydro-6H-quinoxalin-5-one (740 mg, 5 mmol) as the startingmaterial, the title compound was prepared as a brown solid.

¹H NMR (CDCl₃) δ 9.15 (br. 1H), 8.20-6.90 (m, 5H), 3.85 (s, 3H), 3.35(t, J=3.5 Hz, 2H), 3.15 (t, J=3.5 Hz, 2H)

MS (m/z): MH+ (252)

Example 138 8-Methoxy-11-methyl-5,11-dihydro-6H-pyrido[3,2-a]carbazole

Following the procedure described in Example 125, using8-methoxy-5,11-dihydro-6H-pyrazino[2,3-a]carbazole (500 mg, 2 mmol) asthe starting material, the title compound was prepared as a pale solid.

¹H NMR (CDCl₃) δ 8.05-7.05 (m, 5H), 3.85 (s, 3H), 3.35 (t, J=3.5 Hz,2H), 3.15 (t, J=3.5 Hz, 2H)

Example 13911-methyl-6,11-dihydro-5-thia-1,4,11-triaza-benzo[a]fluoren-8-ol

Following the procedure described in Example 126, using8-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (260 mg,1 mmol) as the starting material, the title compound was prepared as abrown solid.

1H NMR (CDCl3) δ 9.75 (br, 1H), 8.15-7.25 (m, 3H), 3.85 (s, 3H), 3.35(t, J=3 Hz, 2H), 3.15 (t, J=3 Hz, 2H)

Ms (m/z): MH+ (252), MH− (250)

Example 140[2-(8-methoxy-5,6-dihydro-pyrido[3,2-a]carbazol-11-yl-ethyl]-dimethyl-amine

Following the procedure described in Example 125, using8-methoxy-5,11-dihydro-6H-pyrido[3,2-a]carbazole (1.0 g, 4.0 mmol) andClCH₂CH₂N(Me)₂ (1.0 eq.) as the starting material, the title compoundwas prepared as a brown solid.

¹H NMR (CDCl3) δ 8.40-6.85 (m, 6H), 4.40 (t, J=3 Hz, 2H), 3.85 (s, 3H),3.20 (t, J=3 Hz, 2H), 2.95 (t, J=3 Hz, 2H), 2.75 (t, J=3 Hz, 2H), 2.35(s, 6H)

MS (m/z): MH+ (323)

Example 14111-(2-dimethylamino-ethyl-5,11-dihydro-6H-pyrido[3,2-a]carbazol-9-ol

Following the procedure described in Example 126, using[2-(8-methoxy-5,6-dihydro-pyrido[3,2-a]carbazol-11-yl-ethyl]-dimethyl-amine(1.6 g, 5 mmol) as the starting material, the title compound wasprepared as a brown solid.

¹H NMR (CDCl3) δ 8.40-6.85 (m, 6H), 4.40 (t, J=3 Hz, 2H), 3.45 (s, 1H),3.20 (t, J=3 Hz, 2H), 2.95 (t, J=3 Hz, 2H), 2.75 (t, J=3 Hz, 2H), 2.35(s, 6H)

MS (m/z): MH+ (309)

Example 142 9-methoxy-5,11-dihydro-6H-pyrido[3,2-a]carbazol

Following the procedure described in Example 124, using7,8-dihydro-6H-quinolin-5-one (1.48 g, 10.0 mmol) as the startingmaterial, the title compound was prepared as a brown solid.

¹H NMR (CDCl₃) δ 8.40 (br, 1H), 8.30-6.80 (m, 6H), 3.80 (s, 3H), 3.15(t, J=3.0 Hz, 2H). 3.05 (t, J=3.0 Hz, 2H)

MS (m/z): MH+ (251)

Example 143 9-methoxy-11-methyl-5,11-dihydro-6H-pyrido[3,2-a]carbazole

Following the procedure described in Example 125, using9-methoxy-5,11-dihydro-6H-pyrido[3,2-a]carbazole (1.40 g, 5.6 mmol) asthe starting material, the title compound was prepared as a pale yellowsolid.

¹H NMR (CDCl₃) δ 8.35-6.85 (m, 6H), 3.90 (s, 3H), 3.85 (s, 3H), 3.20 (t,J=3.0 Hz, 2H). 3.00 (t, J=3.0 Hz, 2H)

MS (m/z): MH+ (265)

Example 144 11-Methyl-5,11-dihydro-6H-pyrido[3,2-a]carbazol-9-ol

Following the procedure described in Example 126, using9-methoxy-11-methyl-5,11-dihydro-6H-pyrido[3,2-a]carbazole (320 mg, 1.2mmol) as the starting material, the title compound was prepared as abrown solid.

¹H NMR (MeOH) δ 8.20-6.65 (m, 6H), 3.30 (s, 3H), 3.15 (t, J=3 Hz, 2H),2.95 (t, J=3 Hz, 2H)

MS (m/z): MH+ (251), MH− (249)

Example 145 7-methoxy-5,10-dihydro-4H-thieno[3,2-a]carbazole

Following the procedure described in Example 124, using4-keto-4,5,6,7-tetrahydrothianaphthlene (760 mg, 5.0 mmol) as thestarting material, the title compound was prepared as a brown solid.

1H NMR (CDCl3) δ 7.90 (br, 1H), 7.25-6.80 (m, 5H), 3.85 (s, 3H), 3.10(m, 4H)

Ms (m/z): MH+ (256)

Example 146 7-Methoxy-10-methyl-5,10-dihydro-4H-thieno[3,2-a]carbazole

Following the procedure described in Example 125, using7-methoxy-5,10-dihydro-4H-thieno[3,2-a]carbazole (800 mg, 3.1 mmol) asthe starting material, the title compound was prepared as a brown solid.

Ms (m/z): MH+ (270)

Example 147 10-methyl-5,10-dihydro-4H-thienol[3,2-a]carbazol-7-ol

Following the same procedure described in Example 126, using7-methoxy-10-methyl-5,10-dihydro-4H-thieno[3,2-a]carbazoleas (525 mg),the title compound was prepared as a brown solid.

¹H NMR (CDCl₃) δ 7.72 (d, J=7.5 Hz, 1H), 7.32 (d, J=1.5 Hz, 1H), 7.22(d, J=7.5, 1H), 6.95 (m, 2H), 3.92 (s, 3H), 3.82 (t, J=8.5 Hz, 2H), 3.45(t, J=8.5 Hz, 2H)

MS (m/z): MH+ (256).

Example 148 7-methoxy-3,4,5,10-tetrahydro-pyrrolo[3,2-a]carbazole

Following the procedure described in Example 124, using1,5,6,7-tetrahydro-indol-4-one (675 mg, 5.0 mmol) as the startingmaterial, the title compound was prepared as a brown solid.

1H NMR (CDCl3) δ 7.25-6.60 (m, 5H), 3.85 (s, 3H), 3.00 (t, J=5 Hz, 2H),2.80 (t, J=5 Hz, 2H)

Ms (m/z): MH+ (237)

Example 1493,10-dimethyl-3,4,5,10-tetrahydro-pyrrolo[3,2-a]carbazol-7-ol

Following the procedure described in Example 125, using7-methoxy-3,4,5,10-tetrahydro-pyrrolo[3,2-a]carbazole (474 mg, 2.0 mmol)as the starting material,7-methoxy-3,10-dimethyl-3,4,5,10-tetrahydro-pyrrolo[3,2-a]carbazole asprepared as a crude product. The crude product was then reactedaccording to the procedure as described in Example 126 to yield thetitle compound as a brown solid.

¹H NMR (CDCl₃) δ 7.72 (d, J=7.5 Hz, 1H), 7.40 (d, J=1.5 Hz, 1H), 7.22(d, J=7.5, 1H), 6.85 (m, 2H), 4.05 (s, 3H), 3.02 (t, J=8.5 Hz, 2H), 2.85(t, J=8.5 Hz, 2H)

MS (m/z): MH+ (280)

Example 150 11-Ethyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol

Following the procedure described in Example 58, using11-ethyl-8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (756 mg,2.56 mmol), as the starting material, the title compound was prepared asa brown solid.

MS (m/z): MH⁺ (282), MH⁻ (280)

¹H NMR (CDCl₃) δ 7.96-6.82 (m, 7H), 4.28 (q, J=6.6 Hz, 2H), 4.00 (s,2H), 1.52 (t, J=6.6 Hz, 3H)

Example 1516-[1,4-dithia]-8a-methyl-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-one

3,4,8,8a-tetrahydro-8a-methyl-1,6 (2H, 7H)-naphthalenedione (1.78 g,10.0 mmol) was mixed with 1,2-Bis-trimethylsilanylsulfanyl-ethane (2.38g, 10.0 mmol) in ether (10.0 ml). The reaction was stirred at roomtemperature overnight and then quenched with H₂O, extracted with ethylacetate. Crude product was purified on column chromatography (Hex: ethylacetate, 1:1) to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 5.65 (s, 1H), 3.35 (m, 2H), 3.25- (m, 1H), 2.70-2.50(m, 2H), 2.35-2.00 (m, 7H), 1.75-1.60 (m, 2H), 1.25 (s, 3H)

MS (m/z): M+Na (277)

Example 1523-[1,4-dithia]-8-Methoxy-11b-methyl-2,5,6,11,11b-hexahydro-1H-benzo[a]carbazole

Following the procedure described in Example 4, using4-methoxy-hydrazine6-[1,4-dithia]-8a-methyl-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-one(1.27 g, 5.0 mmol) as the starting material, the title compound wasprepared as a brown solid.

¹H NMR (CDCl₃) δ 7.60 (br, 1H), 7.35-6.70 (m, 3H), 5.70 (s, 1H), 3.80(s, 3H), 3.40-2.30 (m, 12H), 1.40 (s, 3H)

MS (m/z): MH+ (358)

Example 1533-[1,4-dithia]-8-Methoxy-11,11b-methyl-2,5,6,11b-hexahydro-1H-benzo[a]carbazole

Following the procedure described in Example 33, using3-[1,4-dithia]-8-methoxy-11b-methyl-2,5,6,11,11b-hexahydro-1H-benzo[a]carbazolefrom Example 152 (700 mg, 2 mmol) as the starting material, the titlecompound was prepared as a brown solid,

¹H NMR (CDCl₃) δ 7.35-6.70 (m, 3H), 5.70 (s, 1H), 3.80 (s, 3H), 3.75 (s,3H), 3.40-2.10 (m, 12H), 1.40 (s, 3H)

MS (m/z): MH+ (372)

Example 1548-methoxy-11,11b-dimethyl-1,2,5,6,11,11b-hexahydro-benzo[a]carbazol-3-one

A mixture of3-[1,4-dithia]-8-methoxy-11,11b-methyl-2,5,6,11b-hexahydro-1H-benzo[a]carbazole(700 mg, 1.9 mmol) in THF (20 ml) and water (3.0 ml) was mixed withCaCO₃ (0.33 g, 3 mmol) and Hg(ClO₄)₂ (1.5 ml, 2.0 M solution). After 10min at 25° C., the reaction mixture turned a black color. The reactionmixture was filtered though a pad of Celite. The solvent was removed andthe residue was partitioned between EtOAc and water. The organic layerwas washed with brine, dried and concentrated. The crude product waspurified by chromatography to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 7.60 (br, 1H), 7.35-6.75 (m, 3H), 5.90 (s, 1H), 3.80(s, 3H), 3.75 (s, 3H), 3.00-2.20 (m, 8H), 1.65 (s, 3H)

MS (m/z): MH+ (281)

Example 1558-hydroxy-11,11b-dimethyl-1,2,5,6,11,11b-hexahydro-benzo[a]carbazol-3-one

Following the procedure described in Example 58, using8-methoxy-11,11b-dimethyl-1,2,5,6,11,11b-hexahydro-benzo[a]carbazol-3-one(500 mg, 1.8 mmol), as prepared in Example 154, as starting material,the title compound was prepared as a brown solid.

¹H NMR (CDCl3) δ 7.12-6.77 (m, 3H), 5.95 (s, 1H), 4.70 (br, 1H), 3.78(s, 3H), 2.95 (m, 1H), 2.79-2.52 (m, 6H), 2.21 (m, 1H), 1.70 (s, 3H)

Ms (m/z): MH+ (267)

Example 1563-[1,4-dithia]-9-methoxy-11b-methyl-2,3,5,6,11,11b-hexahydro-1H-benzo[a]carbazole

Following the procedure described in Example 4, using3-methoxy-hydrazine and6-[1,4-dithia]-8a-methyl-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-one (0.8g, 3.2 mmol) as the starting materials, the title compound was preparedas a brown solid.

¹H NMR (CDCl₃) δ 7.60 (br, 1H), 7.40-6.70 (m, 3H), 5.70 (s, 1H), 3.80(s, 3H), 3.40-2.30 (m, 12H), 1.40 (s, 3H)

MS (m/z): MH+ (358)

Example 1573-[1,4-dithia]-9-methoxy-11,11b-dimethyl-1,2,5,6,11,11b-hexahydro-benzo[a]carbazole

Following the procedure described in Example 33, using3-[1,4-dithia]-9-methoxy-11b-methyl-2,3,5,6,11,11b-hexahydro-1H-benzo[a]carbazolefrom Example 168 (700 mg, 2 mmol) as the starting material, the titlecompound was prepared as a white solid.

¹H NMR (CDCl₃) δ 7.35-6.70 (m, 3H), 5.70 (s, 1H), 3.80 (s, 3H), 3.75 (s,3H), 3.40-2.30 (m, 12H), 1.45 (s, 3H)

MS (m/z): MH+ (372)

Example 1589-methoxy-11,11b-dimethyl-1,2,5,6,11,11b-hexahydro-benzo[a]carbazol-3-one

Following the procedure described in Example 154, using3-[1,4-dithia]-9-methoxy-11,11b-dimethyl-1,2,5,6,11,11b-hexahydro-benzo[a]carbazolefrom Example 157 (700 mg, 1.9 mmol) as the starting material, the titlecompound was prepared as a white solid.

¹H NMR (CDCl₃) δ 7.45-6.75 (m, 3H), 5.90 (s, 1H), 3.80 (s, 3H), 3.75 (s,3H), 3.00-2.20 (m, 8H), 1.65 (s, 3H)

MS (m/z): MH+ (281)

Example 1599-hydroxy-11,11b-dimethyl-1,2,5,6,11,11b-hexahydro-benzo[a]carbazol-3-one

Following the procedure described in Example 58, using9-methoxy-11,11b-dimethyl-1,2,5,6,11,11b-hexahydro-benzo[a]carbazol-3-one(150 mg, 0.5 mmol), as prepared in Example 158 as the starting material,the title compound was prepared as a white solid.

1H NMR (CDCl3) δ 7.10-6.70 (m, 3H), 5.90 (s, 1H), 4.80 (br, 1H), 3.75(s, 3H), 2.95 (m, 1H), 2.70-2.50 (m, 6H), 2.20 (m, 1H), 1.70 (s, 3H)

Ms (m/z): MH+ (267)

Example 160 1,4a-dimethyl-4,4a,6,7-tetrahydro-1H,3H-quinoline-2,5-dione

1,4a-dimethyl-4,4a,6,7-tetrahydro-1H,3H-quinoline-2,5-dione was preparedas described in WO 00/06167(PCT/US99/16829).

Example 1618-methoxy-4,11b-dimethyl-1,2,4,6,11,11b-hexahydro-pyrido[3,2-a]carbazol-3-one

Following the procedure described in Example 4, using1,4a-dimethyl-4,4a,6,7-tetrahydro-1H,3H-quinoline-2,5-dione (1.0 g, 5.2mmol) as the starting material, the title compound was prepared as awhite solid.

1H NMR (CDCl3) δ 7.25-6.80 (m, 3H), 5.50 (t, J=1.5 Hz, 1H), 3.85 (s,3H), 3.50 (m, 2H), 3.35 (s, 3H), 2.70 (m, 2H), 2.10 (m, 2H), 1.50 (s,3H)

Ms (m/z): MH+ (296)

Example 1628-methoxy-4,11,11b-trimethyl-1,2,4,6,11,11b-hexahydro-pyrido[3,2-a]carbazol-3-one

Following the procedure described in Example 33, using8-methoxy-4,11b-dimethyl-1,2,4,6,11,11b-hexahydro-pyrido[3,2-a]carbazol-3-one(1.0 g, 3.1 mmol) as the starting material, the title compound wasprepared as a white solid.

1H NMR (CDCl3) δ 7.25-6.85 (m, 3H), 5.50 (t, J=1.5 Hz, 1H), 3.85 (s,3H), 3.75 (s, 3H), 3.50 (m, 2H), 3.35 (s, 3H), 2.70 (m, 2H), 2.10-2.35(m, 2H), 1.50 (s, 3H)

Ms (m/z): MH+ (311)

Example 1638-hydroxy-4,11,11b-trimethyl-1,2,4,6,11,11b-hexahydro-pyrido[3,2-a]carbazol-3-one

Following the procedure described in Example 58, using8-methoxy-4,11,11b-trimethyl-1,2,4,6,11,11b-hexahydro-pyrido[3,2-a]carbazol-3-one,as the starting material, the title compound was prepared as a whitesolid.

¹H NMR (CDCl3) δ 7.25-6.85 (m, 3H), 5.50 (t, J=1.5 Hz, 1H), 3.80 (s,3H), 3.50 (m, 2H), 3.20 (s, 3H), 2.70 (m, 2H), 2.10-2.05 (m, 2H), 1.50(s, 3H)

Ms (m/z): MH+ (297)

Example 16411-(2-Dimethylamino-ethyl)-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol

A mixture of[2-(8-methoxy-6H-5-thia-11-aza-benzo[a]fluoren-11-yl)-ethyl]-dimethyl-amine(800 mg, 2.39 mmol) and Pyridine HCl (3.01 g, 23.7 mmol, 10 eq.) washeated to 210° C. for 30 minutes. The reaction mixture was thenpartitioned between EtOAc and saturated NaHCO₃ aqueous solution. Theaqueous layer was extracted three times with EtOAc. The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to yield a crude material. The crude material was purifiedby silica gel (EtOAc to CH₂Cl₂: MeOH 5:1) to yield the title compound asa brown solid.

¹H NMR (CDCl₃) δ 7.75-7.01 (m, 7H), 4.54 (t, 2H, J=7.5 Hz), 4.12 (s,2H), 2.75 (t, 2H, J=7.5 Hz), 2.38 (s, 6H); MS (m/z): MH⁺ (325), MNa⁺(347).

Example 165 Estrogen Receptor α Flash Plate Assay

This assay monitors binding of radiolabeled estrogen to the estrogenreceptor. It is performed on a BioMek 2000 (Beckman). Plates are read ina scintillation counter (Packard TopCount), with decreased counts anindication of binding of a compound to the receptor. The assay was runaccording to the procedure described by Allan, et al., Anal. Biochem.(1999), 275(2), 243-247.

On day one, 100 μL of Estrogen Screening Buffer (ESB, Panvera)containing 5 mM dithiothreitol (DTT, Panvera), 0.5 μg mouseanti-estrogen receptor monoclonal antibody (SRA-1010, Stressgen) and 50ng purified human estrogen receptor a (Panvera) were added to each wellof a 96 well FlashPlate Plus plate crosslinked with goat anti-mouseantibodies (NEN Life Sciences). The plate was sealed and incubated at 4°C. overnight.

On day two, each well was washed three times with 200 μL PBS, pH 7.2, atroom temperature. To each well was then added 98 μL radiolabeledestrogen (0.5 nM, which equals 6 nCi for a 120 Ci/mmol batch, Amersham),diluted in ESB and 5 mM dithiothreitol (DTT). To individual wells werethen added 2.5 μL test compound diluted in 30% (v/v) dimethylsulfoxide/50 mM HEPES, pH 7.5. The wells were mixed three times byaspiration, the plate sealed and incubated at room temperature for onehour. The wells were then counted for 1 min in a TopCount scintillationcounter (Packard).

Example 166 Estrogen Receptor β Fluorescence Polarization Assay

This assay monitors binding of a fluorescent analog of estrogen(Fluormone ES2, Panvera) to the estrogen receptor. Plates are read in afluorometer that can be set to polarization mode. A decrease influorescence relative to vehicle control is an indication of binding ofa compound to the receptor.

It is crucial to avoid introduction of air bubbles into the reaction ineach well of the 96 well plate throughout this procedure. (Bubbles onthe surface of the reaction disrupt light flow, affecting thepolarization reading.) However, it is also crucial to effectively mixthe reaction components upon addition to the well.

On ice, a 2× standard mixture of Assay Buffer (Panvera), 10 nM DTT and40 nM ES2 was prepared. On ice, a 2× reaction mixture of Assay Buffer(Panvera), and 20 nM hER-β (Panvera) and 40 nM ES2 was also prepared.

Dilutions of test compound were prepared in 30% (v/v) dimethylsulfoxide/50 mM HEPES, pH 7.5. At this point, the dilutions were 40× thefinal required concentration.

The standard mixture at 50 μL was then added to each well. The reactionmixture at 48 μL was added to all wells. The compound dilution at 2.5 μLwas added to the appropriate wells. The reaction mixtures were mixedusing a manual pipette, a roll of aluminum foil adhesive cover wasplaced on the plate and the plate incubated at room temperature for 1hour.

Each well on the plate was then read in an LjL Analyst with anexcitation wavelength of 265 nm and an emission wavelength of 538.

Example 167 Androgen Receptor Binding Using Rat Ventral Prostate Cytosol

Male Sprague Dawley or Wistar rats (Charles River, 200-300 g) were usedfor each preparation. The day before preparing the cytosol, the ratswere castrated using standard surgical procedures.

The rats were euthanized by carbon dioxide asphyxiation. The ratprostates were then quickly removed and placed on ice in pre-chilled,pre-weighed 50 mL plastic tubes. No more than five prostates were placedin each tube. The tubes were then weighed and the prostate tissue wetweights calculated.

To the chilled prostate tissue was then added 1 mL/mg tissue of chilledhomogenization buffer. The homogenization buffer was freshly prepared bymixing 10 mM Tris.HCl, pH 7.4, 1 mM sodium molybdate, 1.5 mM EDTA, 1 mMdithiothreitol, 10% (v/v) glycerol and 1% protease inhibitor cocktail(Sigma P 8340).

The prostate tissue was homogenized in a cold room using a pre-chilledPolytron PT3000 homogenizer (Brinkmann). Homogenization was performed ata speed setting of 20, three times for 10 sec bursts. The tubescontaining the prostate tissue was kept on ice while homogenizing. Thehomogenate was allowed to rest on ice for 20 sec between bursts.

The homogenate was then placed into pre-chilled 3 mL polycarbonateultracentrifuge tubes and centrifuged in the TLA-100 rotor of a TL-100ultracentrifuge for 12 min at 100,000 rpm at 4° C. The resultingsupernatant was stored in 1 mL aliquots at −80° C. until needed.

Binding to the androgen receptor was determined according to theprotocol described in Example 164 using the above prepared rat cytosol.

% Inhibition was determined by testing dilutions of the test compound(usually duplicates of 10 μM) in the binding assay. Counts per well weremeasured and percents of inhibition determined. Androgen receptorbinding IC₅₀s were determined by testing serial dilutions of the testcompound (usually duplicate ten half-log dilutions starting at 10 μM) inthe binding assay. Counts per well were measured and IC₅₀s determined bylinear regression.

Example 168 Progesterone Receptor Binding Assay

To a Microflour 2 Black plate (Dynex, Chantilly, Va.), PR ScreeningBuffer, 5 mM dithiothreitol, 40 nM human progesterone receptor ligandbinding domain, and 2 nM Fluormone PL Red (all from Invitrogen,Carlsbad, Calif.) were added, along with test compound at the desiredconcentration. The plate was covered with aluminum foil and incubatedfor 1 hour at room temperature. The plate was then read on an LJLAnalyst fluorescence polarization reader (Molecular Devices, Sunnyvale,Calif.).

% Inhibition was determined by testing dilutions of the test compound(usually duplicates of 10 μM) in the binding assay. Counts per well weremeasured and percents of inhibition determined. Progesteron receptorbinding IC₅₀s were determined by testing serial dilutions of the testcompound (usually duplicate ten half-log dilutions starting at 10 μM) inthe binding assay. Counts per well were measured and IC₅₀s determined bylinear regression.

Example 169 COS-7 Whole-Cell Androgen Receptor Binding Assay, AdenovirusTransduction

Day One:

COS-7 cells were plated in 96-well plates at 20,000 cells per well, in asolution of DMEM/F12 (GIBCO) containing 10% (v/v) charcoal-treated fetalbovine serum (Hyclone) and lacking phenol red. The cells were thenincubated overnight at 37° C. in 5% (v/v) humidified CO₂.

Day Two:

Test compound solutions were prepared by diluting the test compound in100% (v/v) DMSO, if necessary. Each dilution yielded a solution whichwas 625× the final desired test concentration.

Next, 1 mL of DMEM/F12 lacking phenol red was pipetted into each of thewells of a 2-mL 96-well assay block. Then 4 μL of the 625× test compounddilutions were pipetted into each well of the assay block. The wellswere carefully mixed by pipette.

In a 15 mL or 50 mL sterile centrifuge tube, a 2.5 nM dilution oftritiated methyl-trienolone in DMEM/F12 lacking phenol red ([³H]R1881;Perkin-Elmer) was prepared.

In a 15 mL or 50 mL sterile centrifuge tube, a dilution in DMEM/F12 ofthe adenovirus AdEasy+rAR at an moi of 1:50 per well was prepared.

The medium was removed from the 96-well plates by inversion and theplates dried very briefly, inverted, on a sterile towel. As soon aspossible after medium removal, 40 μL of the diluted test compound wasadded to each well, in duplicate. To each well was then added 40 μL ofthe 2.5 nM [³H]R1881 and 20 μL of the diluted adenovirus. The plateswere then incubated for 48 hours at 37° C. in 5% (v/v) humidified CO₂.

Day Four:

The medium was removed from the above incubated plates by inversion anddried. Each well was then washed with 0.35 mL of 1×PBS. The PBS was thenremoved from the plates by inversion and the plates dried.

To each well was then added 50 μL of 0.5% (v/v) Triton X-100 (Sigma) in1×PBS and the plates placed on a rotary shaker for 5 min. The contentsof each well were then transferred to an OptiPlate-96 (Packard)scintillation plate. To each well was then added 0.2 mL of Microscint-20(Packard) and the wells counted on a TopCount (Packard).

Percent inhibition was determined by testing dilutions of the testcompound (usually duplicates of 10 μM) in the binding assay. Counts perwell were measured and percents of inhibition determined. Androgenreceptor binding IC₅₀s were determined by testing serial dilutions ofthe test compound (usually duplicate ten half-log dilutions starting at10 μM) in the binding assay. Counts per well were measured and IC₅₀sdetermined by linear regression.

Representative compounds of the present invention were tested accordingto the procedures described in Examples 165, 166, 167, 168 and 169 abovefor binding to the estrogen, androgen and progestin receptors, withresults as listed in Table 8.

The results listed in Table 8 below, for Estrogen Receptor α andEstrogen Receptor β are listed as IC₅₀s in μM or % Inhibition at 100 μM;for Androgen Receptor, Rat Cystol results are listed as IC₅₀s in μM or %Inhibition at 1 μM; for Androgen Receptor Rat COS-7 Cells, results arelisted as IC₅₀s in μM or % Inhibition at 3 μM; and for ProgestinReceptor, results are listed as IC₅₀s in μM or % Inhibition at 10 μM.

TABLE 8 Androgen Androgen ID No. Estrogen α Estrogen β Rat Cystol RatCos-7 Progestin 3  0.18 μM 8  1.6 μM  0.26 μM   43%   4 μM 9   10 μM 0.85 μM   20%  0.8 μM  3.2 μM 10   10 μM 10 μM −0.2%  7.5 μM   54% 11  14%   −1%  1.5%   22% 12   22%   12%  0.5%  1.5 μM  0.27 μM 14   1 μM15  1.8%   22%  2.4 μM 16  −62%   6 μM 17   4%  8.8%  1.5%  0.8 μM   18%20  −16% 22  −33% 23   3% 24 0.022 μM 0.068 μM 29  −12%   10 μM 30  2.2μM   10 μM  −17% 32   10 μM    5 μM 23.5%  4.5 μM 34  0.25 μM   55% 0.25μM  1.3 μM 0.099 μM 36  5.5% 37   10 μM  0.44 μM 39  0.6 μM 40  2.6 μM42   5%  8.5%  −12%    9 μM 43   1%   15%  −20%  8.4 μM 44  3.2%   20%−9.0%  3.7 μM  1.6 μM 47  2.3 μM  0.76 μM 56.5%   3 μM  1.1 μM 48  0.45μM 0.013 μM  2.1 μM  0.9 μM 50 0.018 μM 0.051 μM 52 −2.5%   2% 9.75%  29% 53  0.62 μM  0.51 μM 39.5%   4 μM  1.2 μM 54  −10% 0.51%  −24%  10 μM 57  −20%   10 μM 61  0.4 μM   10 μM 63   4%  5.5% −1.6%  7.6% 65 8.2%  6.5%  115%  0.3 μM 0.097 μM 68 19.9% 27.8% 14.6%  2.2 μM  5.7 μM69  2.3%  6.8% 13.5%  2.2 μM 70  0.11 μM 0.065 μM  −11%  3.4 μM  3.2 μM71 29.5% 30.5% 97.5%  0.2 μM  2.4 μM 72   27%   32% −9.0%  2.9 μM 73 1.7%  7.7% −7.0%   50% 74  7.8%   15% 54.5% 53.5% 75   10 μM  1.6 μM64.5%  3.4 μM  1.5 μM 76 −0.1%   16%   55%   10 μM  2.7 μM 77  1.2% 8.1% −6.5%  3.1 μM 78   14%   42%   10%  0.91 μM 79  8.25 μM 1.2 0.057μM 80  5.7%  8.7% 94.5% 1.56 μM  0.77 μM 81   16%   11%   63%  1.1 μM 82  16%   18%   97% 0.064 μM 83   11%   22%  0.82 μM 84   4%  1.4%  4.6% 1.7 μM 85   14%   46%   71%  0.6 μM  0.1 μM 86   18%   31%   13%  2.6μM 87   22%   8%  8.5% 10.5% 88   21%   2%  4.9%  6.8% 89  7.5%   14% 5.8%  0.39 μM 91   10%   4%   47%  0.5 μM 38.5% 93   11%   12%   78% 0.3 μM 40.3% 94   11%   7%   19% 21.5% 95   12%   10%   18% 100  0.97μM 0.085 μM   87%  0.9 μM 101   0%   3%   30%   22% 103  2.5%  3.5% −22% 7.65% 105   10 μM  0.63 μM   88%  0.18 μM 106  6.2%  5.4%   12% 1.7 μM 109  3.4%   22%  2.2 μM  5.3 μM 110 6.06%  9.3% 0.93 4.34 111 4.4%  7.6%   14% 112   5%   13%  2.1% 118   2.8 μM  0.09 μM  9.1 μM 119 0.47 μM  0.51 μM 121  1.2 μM 124  1.2 μM 125  6.9%   24%   5 μM  4.6 μM126  4.6 μM  0.91 μM  0.99 μM 133   10%  7.2%   50% 134 2.35%  5.2%   3μM    3 μM

Example 170

As a specific embodiment of an oral composition, 100 mg of the compoundprepared as in Example 163 is formulated with sufficient finely dividedlactose to provide a total amount of 580 to 590 mg to fill a size O hardgel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

We claim:
 1. A method of treating a disorder mediated by one or more sexsteroid hormone receptors, selected from the group consisting of hotflashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, lossof cognitive function, hormone sensitive cancers, hormone sensitivehyperplasia, endometriosis, uterine fibroids, osteoarthritis, prostatecarcinoma, benign prostatic hyperplasia (BPH), hirsitutism, alopecia,anorexia nervosa, breast cancer, acne, AIDS, cachexia, endometriosis,myoma, dysfunctional bleeding, tumors containing steroid receptors, formale contraception, for female contraception, for male performanceenhancement, and for hormone replacement comprising administering to asubject in need thereof a therapeutically effective amount of a compoundof formula (I)

wherein X is selected from the group consisting of —S and NR^(A)—;wherein R^(A) is selected from the group consisting of hydrogen,C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, —C₁₋₄alkyl-NR^(C)R^(D) and-L¹-R⁴-(L²)_(c)-R⁵; R¹ is selected from the group consisting ofhydrogen, hydroxy, C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, —C₁₋₄alkyl-NR^(C)R^(D)and -L¹-R⁴-(L²)_(c)-R⁵;

is a five to seven membered aromatic, partially unsaturated or saturatedring structure, optionally containing one to two heteroatomsindependently selected from O, N or S; wherein the heteroatom(s) are notthe bridge atom(s); a is an integer selected from 0 to 2; R² is selectedfrom the group consisting of halogen, hydroxy, carboxy, oxo, cyano,nitro, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkyl, C₁₋₄alkoxy,halogenated C₁₋₄alkyl, —O-aralkyl, —C(O)—C₁₋₄alkyl, —C(O)O—C₁₋₄alkyl,—OC(O)—C₁₋₄alkyl, —O—SO₂—C₁₋₄alkyl, —O—SO₂-(halogenated C₁₋₄alkyl) and—O—Si(CH₃)₂(t-butyl); b is an integer selected from 0 to 2; R³ isselected from the group consisting of halogen, hydroxy, carboxy, oxo,cyano, nitro, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkyl,C₁₋₄alkoxy, halogenated C₁₋₄alkyl, —O-aralkyl, —C(O)—C₁₋₄alkyl,—C(O)O—C₁₋₄alkyl, —OC(O)—C₁₋₄alkyl, —O—SO₂—C₁₋₄alkyl,—O—SO₂-(halogenated C₁₋₄alkyl) and —O—Si(CH₃)₂(t-butyl); L¹ is selectedfrom the group consisting of —CH₂— and —C(O)—; R⁴ is selected from thegroup consisting of a five to six membered aryl and a five to sixmembered heteroaryl; c is an integer selected from 0 to 1; L² isselected from the group consisting of —C₁₋₄alkyl-, —C₂₋₄alkenyl-,—O—C₁₋₃alkyl-, —S—C₁₋₃alkyl- and —NR^(B)—C₁₋₃alkyl-; wherein R^(B) isselected from hydrogen or C₁₋₄alkyl; R⁵ is selected from the groupconsisting of —NR^(C)R^(D), —C(O)—C₁₋₄alkyl, —CO₂H, —C(O)O—C₁₋₄alkyl and—OC(O)—C₁₋₄alkyl; wherein R^(C) and R^(D) are independently selectedfrom hydrogen or C₁₋₄alkyl; alternatively, R^(C) and R^(D) are takentogether with the nitrogen atom to which they are bound to form a fiveto seven membered aromatic, partially aromatic or saturated ringstructure; wherein the ring structure optionally contains one to twoadditional heteroatoms selected from O, N or S; provided further thatR^(A) and R¹ are not each -L¹-R⁴-(L²)_(c)-R⁵; provided further that whena is 0 and b is 0; then one of R^(A) or R¹ is -L¹-R⁴-(L²)_(c)-R⁵;provided further that when R¹ is hydrogen; and

is phenyl; then at least one of a or b is other than 0; provided furtherthat when X is —NH— or —N(C₁₋₆alkyl)-; R¹ is hydrogen or C₁₋₆alkyl; a is0 to 1; R² is halogen or —C(O)O—C₁₋₄alkyl; b is 1; and R³ is halogen or—C(O)O—C₁₋₄alkyl; then

is other than phenyl; provided further that when X is —O—; R¹ ishydrogen or C₁₋₄alkyl;

is phenyl; a is 0 to 1; b is 0 to 1; and at least one of a or b is 1;then at least one of R² or R³ is other than halogen, cyano, nitro,carboxy or —C(O)O—C₁₋₄alkyl; provided further that when X is —O—;

is phenyl; a is 0; and b is 0; then R¹ is other than—C₁₋₄alkyl-N(C₁₋₄alkyl)₂ or —C₁₋₄alkyl-piperidinyl; provided furtherthat when X is —O—; R¹ is hydrogen;

is pyridyl or thienyl; a is 0; and b is 1 to 2; then R² is other thanoxo, halogen or —C(O)O—C₁₋₄alkyl; provided further that when X is —O—;R¹ is hydrogen or C₁₋₄alkyl;

is pyrrolyl; a is 0; and b is 1 or 2; then R² is other than C₁₋₄alkyl or—C(O)O—C₁₋₄alkyl; provided further that when X is —S—; R¹ is hydrogen,C₁₋₄alkyl, —C₁₋₄alkyl-N(C₁₋₄alkyl)₂, —C₁₋₄alkyl-piperidinyl,—C₁₋₄alkyl-pyrrolidinyl or —C₁₋₄alkyl-morpholinyl;

is phenyl; a is 0 to 2; and b is 0 to 2; then at least one of R² or R³is other than halogen, C₁₋₄alkyl, C₁₋₄alkoxy, cyano, nitro, amino or—C(O)O—C₁₋₄alkyl; or a pharmaceutically acceptable salt thereof.
 2. Themethod of claim 1, wherein the disorder mediated one or more sex steroidhormone receptors in selected from the group consisting of hormonesensitive cancers, hormone sensitive hyperplasia, endometriosis, uterinefibroids, prostate carcinoma, benign prostatic hyperplasia BPH breastcancer, and tumors containing steroid receptors.